CBLc.1096-1G>TPathogenic

Print report

Variant interpretation report

CBL c.1096-1G>T, p.?

NM_005188.3:c.1096-1G>T NP_005179.2:p.? View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About CBL

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 strong (pathogenic) · 1 moderate (pathogenic) · 3 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 5 Pathogenic
Pipeline record: 25 Jun 2026 · version 7.0.0

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): This variant affects the canonical splice acceptor site of CBL intron 7 (c.1096-1G>T), disrupting the AG dinucleotide at position -1. Germline loss-of-function variants in CBL are an established disease mechanism for CBL mutation-associated syndrome (a RASopathy with predisposition to JMML). SpliceAI predicts acceptor loss with a max delta score of 0.99. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice site variants in genes with an established LoF mechanism are assigned PVS1 at full strength.
PS2 (strong): NM_005188.3:c.1096-1G>T has been observed as a de novo occurrence in two unrelated individuals with features consistent with CBL-related RASopathy, with confirmed paternity in both cases. Martinelli et al. (2015) reported this variant as de novo in a sporadic case (patient 827-10) with parental DNA confirmation. Seaby et al. (2017) reported the same variant as de novo in a child with atypical hemolytic uremic syndrome and RASopathy features.
PS3 (supporting): A minigene assay performed by Martinelli et al. (2015) demonstrated that c.1096-1G>T results in aberrant splicing with complete skipping of exon 8, which encodes essential regions of the linker region and RING finger domain. This well-established in vitro functional assay confirms a damaging effect on mRNA processing and protein function. Applied at supporting level because this evidence confirms the null effect already captured by PVS1 rather than providing independent functional evidence of a distinct mechanism.
PM1 (moderate): The c.1096-1G>T variant affects splicing of exon 8, which encodes the linker region and RING finger domain of CBL. Exons 8 and 9 are well-established mutational hotspots: approximately 50% of germline CBL mutations affect Tyr371 within this region, and splice site mutations affecting introns 7 and 8 account for approximately 10% of CBL defects in myeloid malignancies. The affected region is a critical functional domain with a high density of pathogenic variants and no benign variation.
PM2 (supporting): NM_005188.3:c.1096-1G>T is absent from gnomAD v2.1 and gnomAD-Canada v1.0. In gnomAD v4.1, it is observed in a single heterozygous carrier (1/1,590,474 alleles; AF = 6.29e-07, ~0.00006%), well below the PM2 threshold of 0.1%. The variant is absent from all subpopulations except European (non-Finnish) where it is present in 1/1,159,346 alleles.
PP5 (supporting): NM_005188.3:c.1096-1G>T is classified as Pathogenic in ClinVar (Variation ID: 180815) by five clinical laboratories (GeneDx, Laboratory for Molecular Medicine, Ambry Genetics, Invitae/Labcorp, and King Faisal Specialist Hospital). While the review status is 'criteria provided, single submitter' and no expert panel review is available, multiple independent clinical laboratories have reached the same conclusion based on overlapping evidence.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 6 Benign evidence criteria: 0

Pathogenic criteria applied · 6

PVS1Very strong

PVS1 · very strong

This variant affects the canonical splice acceptor site of CBL intron 7 (c.1096-1G>T), disrupting the AG dinucleotide at position -1. Germline loss-of-function variants in CBL are an established disease mechanism for CBL mutation-associated syndrome (a RASopathy with predisposition to JMML). SpliceAI predicts acceptor loss with a max delta score of 0.99. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice site variants in genes with an established LoF mechanism are assigned PVS1 at full strength.

PS2Strong

PS2 · strong

NM_005188.3:c.1096-1G>T has been observed as a de novo occurrence in two unrelated individuals with features consistent with CBL-related RASopathy, with confirmed paternity in both cases. Martinelli et al. (2015) reported this variant as de novo in a sporadic case (patient 827-10) with parental DNA confirmation. Seaby et al. (2017) reported the same variant as de novo in a child with atypical hemolytic uremic syndrome and RASopathy features.

PS3Supporting

PS3 · supporting

A minigene assay performed by Martinelli et al. (2015) demonstrated that c.1096-1G>T results in aberrant splicing with complete skipping of exon 8, which encodes essential regions of the linker region and RING finger domain. This well-established in vitro functional assay confirms a damaging effect on mRNA processing and protein function. Applied at supporting level because this evidence confirms the null effect already captured by PVS1 rather than providing independent functional evidence of a distinct mechanism.

PM1Moderate

PM1 · moderate

The c.1096-1G>T variant affects splicing of exon 8, which encodes the linker region and RING finger domain of CBL. Exons 8 and 9 are well-established mutational hotspots: approximately 50% of germline CBL mutations affect Tyr371 within this region, and splice site mutations affecting introns 7 and 8 account for approximately 10% of CBL defects in myeloid malignancies. The affected region is a critical functional domain with a high density of pathogenic variants and no benign variation.

PM2Supporting

PM2 · supporting

NM_005188.3:c.1096-1G>T is absent from gnomAD v2.1 and gnomAD-Canada v1.0. In gnomAD v4.1, it is observed in a single heterozygous carrier (1/1,590,474 alleles; AF = 6.29e-07, ~0.00006%), well below the PM2 threshold of 0.1%. The variant is absent from all subpopulations except European (non-Finnish) where it is present in 1/1,159,346 alleles.

PP5Supporting

PP5 · supporting

NM_005188.3:c.1096-1G>T is classified as Pathogenic in ClinVar (Variation ID: 180815) by five clinical laboratories (GeneDx, Laboratory for Molecular Medicine, Ambry Genetics, Invitae/Labcorp, and King Faisal Specialist Hospital). While the review status is 'criteria provided, single submitter' and no expert panel review is available, multiple independent clinical laboratories have reached the same conclusion based on overlapping evidence.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PS2 strong, PS3 supporting, PM1 moderate, PM2 supporting, PP5 supporting; combination = 1 very strong + 1 strong + 1 moderate + 3 supporting, which maps to Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

1 / 1,590,474 alleles

gnomAD v4.1: 1 / 1,590,474 alleles. Recorded AF 6.28743e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.990 maximum delta

Recorded SpliceAI maximum delta score: 0.990. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

5 reported laboratory submissions

5 Pathogenic.

Applied · PP5 → ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

Applied · PS3 → OncoKB ↗

Somatic evidence

8 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV50635311, n = 8 times).

Context only COSMIC ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 6 met · 4 not met · 4 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_005188.3:c.1096-1G>T is a canonical splice acceptor variant in CBL, disrupting the AG dinucleotide at the intron 7 / exon 8 boundary.

CBL loss-of-function is an established disease mechanism for a RASopathy phenotype with predisposition to juvenile myelomonocytic leukemia (CBL mutation-associated syndrome).

The variant has been observed as a de novo occurrence in two unrelated individuals with features consistent with CBL-related RASopathy, with confirmed paternity in both cases.

A minigene assay demonstrated that c.1096-1G>T results in complete skipping of exon 8, which encodes the linker region and RING finger domain critical for CBL E3 ubiquitin ligase function.

The variant affects the RING finger domain / linker region (exons 8-9), a well-established mutational hotspot where approximately 50% of germline CBL mutations cluster and no benign variation is observed.

The variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and observed in a single heterozygous carrier in gnomAD v4.1 (1/1,590,474 alleles; AF = 0.00006%).

This variant is classified as Pathogenic in ClinVar (Variation ID: 180815) by five independent clinical laboratories.

Applying generic ACMG/AMP 2015 combination rules: PVS1 (very_strong) + PS2 (strong) + PM1 (moderate) + PS3 (supporting) + PM2 (supporting) + PP5 (supporting) is sufficient for a Pathogenic classification.

Met · 6

PVS1 Very strongThis variant affects the canonical splice acceptor site of CBL intron 7 (c.1096-1G>T), disrupting the AG dinucleotide at position -1. Germline loss-of-function variants in CBL are an established disease mechanism for CBL mutation-associated syndrome (a RASopathy with predisposition to JMML). SpliceAI predicts acceptor loss with a max delta score of 0.99. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice site variants in genes with an established LoF mechanism are assigned PVS1 at full strength. Details ▾Hide ▴

Evidence considered

Canonical splice acceptor site disruption at intron 7 / exon 8 boundary (AG>AT)
CBL germline LoF is an established disease mechanism for RASopathy (PVS1 gene gate: eligible)
SpliceAI delta score 0.99 (acceptor loss)
Minigene assay confirms complete skipping of exon 8 (Martinelli 2015)

Sources

pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗spliceai ↗PMID:25952305 ↗

PS2 StrongNM_005188.3:c.1096-1G>T has been observed as a de novo occurrence in two unrelated individuals with features consistent with CBL-related RASopathy, with confirmed paternity in both cases. Martinelli et al. (2015) reported this variant as de novo in a sporadic case (patient 827-10) with parental DNA confirmation. Seaby et al. (2017) reported the same variant as de novo in a child with atypical hemolytic uremic syndrome and RASopathy features. Details ▾Hide ▴

Evidence considered

De novo in case 827-10
parental DNA confirmed (Martinelli 2015
Table 1)
De novo in proband with RASopathy features (Seaby 2017)
Consistent with ClinVar submission evidence signals for de novo

Sources

PMID:25952305 ↗PMID:28589114 ↗clinvar ↗

PS3 SupportingA minigene assay performed by Martinelli et al. (2015) demonstrated that c.1096-1G>T results in aberrant splicing with complete skipping of exon 8, which encodes essential regions of the linker region and RING finger domain. This well-established in vitro functional assay confirms a damaging effect on mRNA processing and protein function. Applied at supporting level because this evidence confirms the null effect already captured by PVS1 rather than providing independent functional evidence of a distinct mechanism. Details ▾Hide ▴

Evidence considered

Minigene assay in COS1 cells: c.1096-1G>T causes complete skipping of exon 8 (Martinelli 2015
Figure 2B)

Sources

PMID:25952305 ↗

PM1 ModerateThe c.1096-1G>T variant affects splicing of exon 8, which encodes the linker region and RING finger domain of CBL. Exons 8 and 9 are well-established mutational hotspots: approximately 50% of germline CBL mutations affect Tyr371 within this region, and splice site mutations affecting introns 7 and 8 account for approximately 10% of CBL defects in myeloid malignancies. The affected region is a critical functional domain with a high density of pathogenic variants and no benign variation. Details ▾Hide ▴

Evidence considered

Exons 8-9 encode the RING finger domain and linker region — a known mutational hotspot (Martinelli 2015)
Approximately 10% of CBL defects in myeloid malignancies are splice site mutations affecting introns 7-8 (Kales et al. 2010
cited in Martinelli 2015)
Affected region has no benign variation and is critical for E3 ubiquitin ligase function

Sources

PMID:25952305 ↗

PM2 SupportingNM_005188.3:c.1096-1G>T is absent from gnomAD v2.1 and gnomAD-Canada v1.0. In gnomAD v4.1, it is observed in a single heterozygous carrier (1/1,590,474 alleles; AF = 6.29e-07, ~0.00006%), well below the PM2 threshold of 0.1%. The variant is absent from all subpopulations except European (non-Finnish) where it is present in 1/1,159,346 alleles. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (exomes)
gnomAD v4.1: 1/1
590
474 alleles (AF = 0.00006%)
Absent from gnomAD-Canada v1.0

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP5 SupportingNM_005188.3:c.1096-1G>T is classified as Pathogenic in ClinVar (Variation ID: 180815) by five clinical laboratories (GeneDx, Laboratory for Molecular Medicine, Ambry Genetics, Invitae/Labcorp, and King Faisal Specialist Hospital). While the review status is 'criteria provided, single submitter' and no expert panel review is available, multiple independent clinical laboratories have reached the same conclusion based on overlapping evidence. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 180815: Pathogenic
5 clinical laboratories
Multiple independent submitters reaching same classification

Still missing

No ClinGen expert panel review available

Sources

clinvar ↗

Not met · 4 · evaluated, threshold not reached

BS2 The variant is observed in a single heterozygous carrier in gnomAD v4.1 (1/1,590,474 alleles). For a fully penetrant dominant disorder, a single observation in a population database does not provide sufficient evidence for a benign interpretation. The carrier may have subclinical features or represent incomplete penetrance, which has been described in CBL-related disorders. Details ▾Hide ▴

Evidence considered

Single heterozygous observation in gnomAD v4.1 insufficient for BS2 in dominant disorder

Sources

gnomad_v4 ↗

BS3 Well-established in vitro functional studies (minigene assay, Martinelli 2015) demonstrate that c.1096-1G>T causes aberrant splicing with complete skipping of exon 8, supporting a damaging rather than benign effect. BS3 requires functional studies showing no damaging effect. Details ▾Hide ▴

Evidence considered

Minigene assay demonstrates aberrant splicing with exon 8 skipping (Martinelli 2015)

Sources

PMID:25952305 ↗

BP4 Multiple in silico tools predict a damaging effect on splicing. SpliceAI predicts acceptor loss with a max delta score of 0.99. BP4 requires multiple lines of computational evidence suggesting no impact; the available evidence supports the opposite conclusion. Details ▾Hide ▴

Evidence considered

SpliceAI delta score 0.99 (acceptor loss) — predicts damaging
not benign

Sources

spliceai ↗

BP6 ClinVar classifies this variant as Pathogenic (Variation ID: 180815), not Benign or Likely Benign. BP6 requires classification as benign by a reputable source. Details ▾Hide ▴

Evidence considered

ClinVar classification is Pathogenic — does not support BP6

Sources

clinvar ↗

Not assessed · 4 · no assessment recorded

PS4 Insufficient data to calculate a statistically significant difference in variant prevalence between affected individuals and the general population. While the variant has been reported in multiple affected individuals through ClinVar submissions and published cases, formal case-control comparison is not available. Details ▾Hide ▴

Evidence considered

ClinVar lists 6 submissions (5 clinical labs) classifying as Pathogenic
No formal case-control prevalence data available

Still missing

No case-control prevalence data available for statistical comparison

Sources

clinvar ↗

PP1 No segregation data are available for this variant. The two reported de novo cases are sporadic and no multi-generational families with this variant have been described. Details ▾Hide ▴

Still missing

No family segregation data available

PP4 CBL-related RASopathy has overlapping features with Noonan syndrome and other RASopathies; the phenotype is not sufficiently specific to a single genetic etiology to apply PP4. Clinical features of reported cases include prenatal pleural effusions/hydrops, feeding difficulties, failure to thrive, short stature, hypotonia, psychomotor retardation, and mild pulmonary valve stenosis. Details ▾Hide ▴

Evidence considered

CBL mutation-associated syndrome phenotype overlaps with Noonan syndrome and other RASopathies

Still missing

Phenotype not specific to a single gene

Sources

PMID:25952305 ↗PMID:28589114 ↗

BS4 No segregation data are available to assess for lack of cosegregation with disease in affected families. The reported cases are sporadic de novo occurrences; no multi-generational families have been described. Details ▾Hide ▴

Still missing

No family segregation data available

Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies to a missense variant at the same amino acid position as a known pathogenic missense change. This is a canonical splice site variant and does not produce a defined amino acid change. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a different pathogenic missense change at the same amino acid residue. This is a canonical splice site variant affecting intron 7; it does not produce a defined amino acid change and no classic same-residue comparator can be established. The pm5_candidates pipeline confirmed no eligible comparators. Details ▾Hide ▴

Evidence considered

PM5 pipeline: not_applicable (cannot parse missense residue from variant consequence p.?)

Sources

pm5_candidates

PM6 N/APM6 applies when a variant is assumed de novo but paternity/maternity has not been confirmed. PS2 has already been applied with confirmed paternity in both reported de novo cases; PM6 is not applied when the higher-level PS2 criterion is met. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a canonical splice site variant, not a missense change. Details ▾Hide ▴

No further detail was recorded.

PP3 N/AMultiple in silico tools support a damaging effect (SpliceAI max delta 0.99, acceptor loss). However, under ClinGen SVI PVS1 recommendations, PP3 should not be applied for the same splice prediction evidence already captured by PVS1 for canonical splice variants. The splice effect is already accounted for under PVS1. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.99 (acceptor loss)
Per PVS1 variant assessment: do not stack PP3 for same splice-effect prediction

Sources

spliceai ↗pvs1_variant_assessment

BA1 N/ABA1 requires an allele frequency >1% in population databases. The variant has an allele frequency of 6.29e-07 (0.00006%) in gnomAD v4.1, far below the 1% threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 6.29e-07 (0.00006%)
well below 1%

Sources

gnomad_v4 ↗

BS1 N/ABS1 requires an allele frequency >0.3% in population databases. The variant has an allele frequency of 6.29e-07 (0.00006%) in gnomAD v4.1, far below the 0.3% threshold. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 6.29e-07 (0.00006%)
well below 0.3%

Sources

gnomad_v4 ↗

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a canonical splice site variant, not a missense change. Details ▾Hide ▴

No further detail was recorded.

BP2 N/ABP2 applies to a variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. No such observations have been reported for this variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASkipped: trivially not applicable. BP3 applies to in-frame deletions/insertions in repetitive regions without known function; this variant is a canonical splice site substitution. Details ▾Hide ▴

No further detail was recorded.

BP5 N/ABP5 applies when a variant is found in a case with an alternate molecular basis for disease. No such observation has been reported for this variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants for which splicing prediction algorithms predict no impact. This variant is a canonical splice site substitution at the intron 7 acceptor site (c.1096-1G>T), not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 (also known as PM5) applies to a novel missense change at an amino acid residue where a different pathogenic missense change has been previously observed. This is a canonical splice site variant, not a missense change, and does not produce a defined amino acid substitution. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: CBL
Transcript: NM_005188.3
Coding (HGVS c.): NM_005188.3:c.1096-1G>T
Protein (HGVS p.): NP_005179.2:p.?
GRCh38: chr11:119278165 G>T
GRCh37: chr11:119148875 G>T
ClinVar: 180815
COSMIC: COSV50635311

Gene diagram

Every interpreted variant in CBL, mapped onto the exon structure of NM_005188.3. Select a row to find it on the plot.

CBLNM_005188.3

Fetching transcript structure from UCSC…

Exons

—

Transcript span

—

Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in CBL — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 1 / 1,590,474 alleles AF 6.29e-07 · 0 homozygotes

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.3e-07 · 1 / 1,590,474 alleles · 0 hom

European (non-Finnish)1 / 1,159,346

8.6e-07

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.28743e-07; MAF= 0.00006%, 1/1590474 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.62555e-07; MAF= 0.00009%, 1/1159346 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +1 bp

0.990

SpliceAI acceptor gainat +25 bp

0.030

SpliceAI donor lossat +132 bp

0.380

SpliceAI donor gainat +232 bp

0.000

Pangolin splice lossmagnitude shown

-0.840

Pangolin splice gain

0.030

Other predictors

REVEL: Not available
BayesDel: 0.393

How the predictions were used

Evidence considered

SpliceAI delta score 0.99 (acceptor loss) — predicts damaging
not benign

Sources

spliceai ↗

Evidence considered

SpliceAI max delta 0.99 (acceptor loss)
Per PVS1 variant assessment: do not stack PP3 for same splice-effect prediction

Sources

spliceai ↗pvs1_variant_assessment

No further detail was recorded.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.393226.

9 paper records listed. 2 cited in the classification.

Cited in the classification

Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations.

Martinelli S et al. · 2015 Aug

Reports c.1096-1G>T as a de novo heterozygous splice site variant in a boy (case 827-10) with prenatal pleural effusions/hydrops, severe feeding difficulties, failure to thrive, short stature, hypotonia, psychomotor retardation, splenomegaly, and mild pulmonary valve stenosis. Minigene assay in COS1 cells demonstrated that c.1096-1G>T causes complete skipping of exon 8, which encodes the linker region and RING finger domain. Parental DNA confirmed de novo origin.
→ PVS1 → PS2 → PS3 → PM1 Names this variant
PMID 25952305 ↗
Source detail

The c.1096-1G>T transversion found in case 827-10 had not been previously described... Sequencing of the processed transcript RT-PCR products revealed aberrant splicing of the mutant allele, resulting in loss of the entire exon 8.

Location Results: Mutation analysis (paragraphs 1-3); Molecular characterization of splice site mutations (paragraph 2); Clinical features (paragraph 4); Figure 2B

Context Minigene assay using pSPL3 exon trapping vector, transiently transfected in COS1 cells
Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm.

Seaby EG et al. · 2017

Reports a de novo heterozygous CBL c.1096-1G>T splice site variant identified by whole-genome sequencing in a child with atypical hemolytic uremic syndrome. The variant was predicted pathogenic and considered the likely explanation for RASopathy features. The paper highlights the expanding clinical spectrum of CBL-related disorders.
→ PS2 Names this variant
PMID 28589114 ↗
Source detail

Filtering parameters reduced 51 variants to one heterozygous splicing variant in CBL (c.1096-1G>T) predicted to be pathogenic following application of the American College of Medical Genetics and Genomics guidelines.

Location Case presentation; Figure 1 legend

Other recorded publications

Splicing in action: assessing disease causing sequence changes.

Baralle D et al. · 2005

Review article on splicing mechanisms and disease-causing sequence changes. Discusses general principles of splice site mutations, pseudo splice site activation, and exon skipping. NM_005188.3:c.1096-1G>T was not identified in this paper.
Does not name this variant
PMID 16199547 ↗
Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.

Niemeyer CM et al. · 2010

Landmark paper establishing germline CBL mutations as a cause of developmental abnormalities and JMML predisposition. Describes missense mutations in the RING finger domain and linker region. Mentions c.1096-1G>C (not c.1096-1G>T) in a supplementary table. The specific variant NM_005188.3:c.1096-1G>T was not identified in this paper.
Does not name this variant
PMID 20694012 ↗
A systematic approach to assessing the clinical significance of genetic variants.

Methods paper describing a systematic approach to assessing clinical significance of genetic variants using a scoring framework. NM_005188.3:c.1096-1G>T was not identified in this paper.
Does not name this variant
PMID 24033266 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

ACMG/AMP standards and guidelines for interpretation of sequence variants. Provides the framework for variant classification but does not discuss specific variants. NM_005188.3:c.1096-1G>T was not identified in this paper.
Does not name this variant
PMID 25741868 ↗
Pan-cancer repository of validated natural and cryptic mRNA splicing mutations.

No paper-specific finding is recorded.

PMID 31275557 ↗
Noonan Syndrome.

Adam MP et al. · 1993

No paper-specific finding is recorded.

PMID 20301303 ↗
2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).

Authors/Task Force members et al. · 2014

No paper-specific finding is recorded.

PMID 25173338 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,590,474 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.990 Open source ↗

ClinVar 5 Pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories). (ClinVarID = 180815)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.393226.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV50635311, n = 8 times).