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KITc.1990+8C>TLikely benign
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Variant interpretation report

KIT c.1990+8C>T, p.?

NM_000222.2:c.1990+8C>T NP_000213.1:p.? View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About KIT

No gene-level summary was recorded for this case.

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: 1 Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00279%, v4.1 AF=0.00178%), well below the 0.1% non-VCEP PM2 threshold. One homozygote is observed in each gnomAD version (South Asian subpopulation), which is noted but does not disqualify PM2 at this allele frequency.

Benign criteria applied · 2
BP4Supporting
BP4 · supporting

SpliceAI predicts no significant splicing impact for this intronic variant (max delta score=0.02). While REVEL and BayesDel are unavailable for intronic variants, SpliceAI is the primary relevant in silico tool for splice region variants and supports a benign interpretation.

BP6Supporting
BP6 · supporting

This variant is classified as Likely benign in ClinVar (VC ID 415791) by a clinical testing laboratory (Labcorp Genetics/Invitae), which constitutes a reputable source reporting the variant as benign.

Recorded classification: Likely benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign, BP6 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.

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
28 / 1,574,512 alleles

gnomAD v4.1: 28 / 1,574,512 alleles. Recorded AF 1.77833e-05. Recorded homozygote count 1.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.79394e-05; MAF= 0.00279%, 7/250542 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 6.53381e-05; MAF= 0.00653%, 2/30610 alleles, homozygotes = 1); grpmax FAF= 1.082e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
No screenshot for this evidence
Functional evidence
Not recorded

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

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

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

29 criteria with recorded statuses: 3 met · 4 not met · 11 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000222.2:c.1990+8C>T is an intronic variant at position +8 in intron 13 of KIT, classified as Likely benign based on the generic ACMG/AMP 2015 framework (PMID:25741868).

SpliceAI predicts no significant splicing impact (max delta score=0.02), meeting BP4 at supporting benign level.

The variant is classified as Likely benign in ClinVar (VC ID 415791) by Labcorp Genetics/Invitae, meeting BP6 at supporting benign level.

The variant is present at extremely low frequency in gnomAD (v2.1 AF=0.00279%, v4.1 AF=0.00178%), meeting PM2 at supporting pathogenic level.

With two supporting benign criteria (BP4, BP6) and one supporting pathogenic criterion (PM2), the net evidence meets the generic ACMG/AMP threshold for Likely benign (≥2 supporting benign criteria).

Met · 3

PM2 SupportingThis variant is present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00279%, v4.1 AF=0.00178%), well below the 0.1% non-VCEP PM2 threshold. One homozygote is observed in each gnomAD version (South Asian subpopulation), which is noted but does not disqualify PM2 at this allele frequency. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 7/250
  • 542 alleles (AF=0.00279%)
  • gnomAD v4.1: 28/1
  • 574
  • 512 alleles (AF=0.00178%)
  • grpmax FAF=1.082e-05
Still missing
  • One homozygote observed in South Asian subpopulation in both gnomAD v2.1 and v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingSpliceAI predicts no significant splicing impact for this intronic variant (max delta score=0.02). While REVEL and BayesDel are unavailable for intronic variants, SpliceAI is the primary relevant in silico tool for splice region variants and supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02 (no splice impact predicted)
Still missing
  • Only SpliceAI available for intronic variant
  • no additional orthogonal in silico predictors
Sources
spliceai ↗
BP6 SupportingThis variant is classified as Likely benign in ClinVar (VC ID 415791) by a clinical testing laboratory (Labcorp Genetics/Invitae), which constitutes a reputable source reporting the variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign
  • submitter: Labcorp Genetics (formerly Invitae)
  • review status: criteria provided
  • single submitter
Still missing
  • Single submitter only
  • no expert panel review
Sources
clinvar ↗

Not met · 4 · evaluated, threshold not reached

PP3 Computational evidence does not support a deleterious effect. SpliceAI predicts no significant splicing impact (max delta=0.02). REVEL and BayesDel scores are not available for this intronic variant, and HCI prior does not cover KIT. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02 (no splice impact)
  • REVEL/BayesDel/HCI not scored for intronic variants
Sources
spliceai ↗
PP5 PP5 requires a reputable source reporting the variant as pathogenic. ClinVar reports this variant as Likely benign (1 clinical laboratory, criteria provided single submitter, VC ID 415791). No reputable source reports it as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign
  • not pathogenic
Sources
clinvar ↗
BA1 BA1 requires allele frequency >1% in any population. The highest subpopulation frequency is 0.00886% in South Asian (gnomAD v4.1), far below the 1% threshold. Details ▾Hide ▴
Evidence considered
  • Highest subpopulation AF: 0.00886% (SAS
  • gnomAD v4.1)
  • total AF: 0.00279% (v2.1)
  • 0.00178% (v4.1)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 BS1 threshold for non-VCEP is AF >0.3%. The variant allele frequency in gnomAD is 0.00279% (v2.1) and 0.00178% (v4.1), well below the 0.3% threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD total AF: 0.00279% (v2.1)
  • 0.00178% (v4.1)
  • grpmax FAF=1.082e-05
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 11 · no assessment recorded

PS2 No de novo data with confirmed maternity and paternity were identified in ClinVar submissions or the literature for this variant. Details ▾Hide ▴
Still missing
  • No de novo observations available for this variant
PS3 No well-established functional studies were identified for this variant. The single paper retrieved for functional theme (PMID:23852704) is a tumor marker guideline and does not mention this variant. Details ▾Hide ▴
Still missing
  • No variant-specific functional studies available
PS4 No case-control or cohort data demonstrating enrichment of this variant in affected individuals were identified. Literature-tagged papers (PMID:22685257, 23852704, 25394175, 28492532) are general guidelines/reviews that do not mention this specific variant. Details ▾Hide ▴
Still missing
  • No case-control or affected-individual prevalence data available
PM6 PM6 requires a de novo observation without confirmation of maternity and paternity. No de novo data were identified in ClinVar submissions or the literature for this variant. Details ▾Hide ▴
Still missing
  • No de novo observations available
PP1 No cosegregation data in affected families were identified for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 No patient phenotype or family history data were provided for this variant. Cannot assess whether the clinical presentation is highly specific for a KIT-related disorder. Details ▾Hide ▴
Still missing
  • No patient phenotype or family history data available
BS2 A homozygous individual is observed in gnomAD (South Asian subpopulation), which is notable for an autosomal dominant KIT-related disorder. However, gnomAD is a general population database and does not confirm the individual is a healthy adult with full expected penetrance. Without phenotype confirmation, BS2 cannot be reliably applied or excluded. Details ▾Hide ▴
Evidence considered
  • One homozygote observed in South Asian subpopulation in both gnomAD v2.1 and v4.1
Still missing
  • Cannot confirm homozygote is a healthy adult
  • phenotype data unavailable
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional studies demonstrating no damaging effect were identified for this variant. The SpliceAI delta score of 0.02 suggests no splicing impact but does not alone constitute a well-established functional study. The literature-tagged functional paper (PMID:23852704) does not mention this variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02 (predictive
  • not a functional study)
Still missing
  • No variant-specific functional studies available
Sources
spliceai ↗
BS4 No segregation data in affected families are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 No data on cis/trans phasing with pathogenic variants are available for this variant. Details ▾Hide ▴
Still missing
  • No phasing data with pathogenic variants available
BP5 BP5 requires observation of the variant in a case with an alternate molecular basis for disease. No such data are available for this variant. Details ▾Hide ▴
Still missing
  • No data on alternate molecular basis in carriers
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000222.2:c.1990+8C>T is an intronic variant at position +8, not a canonical ±1,2 splice site variant. Per ClinGen SVI PVS1 framework (PMC6185798), this variant does not fall into any null-variant bucket and is not eligible for PVS1 assessment. Details ▾Hide ▴
Evidence considered
  • Intronic variant at +8 position
  • not a predicted null variant
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/APS1 requires a same amino acid change from a different nucleotide change. This is an intronic variant with no amino acid change, therefore PS1 does not apply. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • no amino acid change
PM1 N/APM1 applies to variants located in a mutational hot spot or critical functional domain. NM_000222.2:c.1990+8C>T is an intronic variant at +8 in intron 13, not located in a coding functional domain or recognized mutational hot spot. Details ▾Hide ▴
Evidence considered
  • Intronic variant at +8
  • not in a coding functional domain
PM3 N/ASkipped per instruction: PM3 applies to recessive disorders and requires observation in trans with a pathogenic variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped per instruction: PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. This is a single nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a different missense change at the same residue previously established as pathogenic. This is an intronic variant with no protein residue; same-residue missense comparator semantics cannot be applied. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • no amino acid residue to compare
Sources
pm5_candidates
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 an intronic variant, not a missense change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • not a missense change
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_000222.2:c.1990+8C>T is an intronic variant, not a missense change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • not a missense change
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This variant is a single nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
  • Single nucleotide substitution
  • not an in-frame indel
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact and non-conserved nucleotide. NM_000222.2:c.1990+8C>T is an intronic variant, not a synonymous coding change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • not a synonymous coding change
PS5 N/APS5 requires a reputable source reporting the variant as pathogenic. The only ClinVar submission classifies this variant as Likely benign, not pathogenic. No other source reports it as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign (single submitter)
  • no pathogenic report available
Sources
clinvar ↗

Identifiers

Gene
KIT
Transcript
NM_000222.2
Coding (HGVS c.)
NM_000222.2:c.1990+8C>T
Protein (HGVS p.)
NP_000213.1:p.?
GRCh38
chr4:54728129 C>T
GRCh37
chr4:55594295 C>T
ClinVar
415791

Gene diagram

Every interpreted variant in KIT, mapped onto the exon structure of NM_000222.2. Select a row to find it on the plot.

KITNM_000222.2
Fetching transcript structure from UCSC…
gnomAD v4.1 28 / 1,574,512 alleles AF 1.78e-05 · 1 homozygotes · FAF 4.4e-05
gnomAD v2.1 7 / 250,542 alleles AF 2.79e-05 · 1 homozygotes · FAF 1.08e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.8e-05 · 28 / 1,574,512 alleles · 1 hom · FAF 4.4e-05
South Asian8 / 90,300 8.9e-051 hom
Admixed American2 / 59,918 3.3e-05
European (non-Finnish)18 / 1,144,066 1.6e-05
0 alternate alleles recorded in 7 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 2.8e-05 · 7 / 250,542 alleles · 1 hom · FAF 1.1e-05
South Asian2 / 30,610 6.5e-051 hom
Admixed American2 / 34,482 5.8e-05
European (non-Finnish)3 / 113,108 2.7e-05
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.77833e-05; MAF= 0.00178%, 28/1574512 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 8.85936e-05; MAF= 0.00886%, 8/90300 alleles, homozygotes = 1); grpmax FAF= 4.401e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.79394e-05; MAF= 0.00279%, 7/250542 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 6.53381e-05; MAF= 0.00653%, 2/30610 alleles, homozygotes = 1); grpmax FAF= 1.082e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -100 bp
0.010
SpliceAI acceptor gainat +154 bp
0.000
SpliceAI donor lossat +30 bp
0.020
SpliceAI donor gainat +284 bp
0.010
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingSpliceAI predicts no significant splicing impact for this intronic variant (max delta score=0.02). While REVEL and BayesDel are unavailable for intronic variants, SpliceAI is the primary relevant in silico tool for splice region variants and supports a benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02 (no splice impact predicted)
Still missing
  • Only SpliceAI available for intronic variant
  • no additional orthogonal in silico predictors
Sources
spliceai ↗
PP3 Computational evidence does not support a deleterious effect. SpliceAI predicts no significant splicing impact (max delta=0.02). REVEL and BayesDel scores are not available for this intronic variant, and HCI prior does not cover KIT. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02 (no splice impact)
  • REVEL/BayesDel/HCI not scored for intronic variants
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact and non-conserved nucleotide. NM_000222.2:c.1990+8C>T is an intronic variant, not a synonymous coding change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • not a synonymous coding change

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.
    Duffy MJ et al. · 2014
    Guideline review of tumor markers in colorectal cancer, gastric cancer, and gastrointestinal stromal tumors. NM_000222.2:c.1990+8C>T was not identified in the full text.
    Does not name this variant
    PMID 23852704 ↗
  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    ACMG/NSGC practice guideline for cancer predisposition assessment referral indications. This is a general clinical guideline that does not discuss individual variants.
    Does not name this variant
    PMID 25394175 ↗
  • The UK NEQAS for Molecular Genetics scheme for gastrointestinal stromal tumour: findings and recommendations following four rounds of circulation.
    Wong NA et al. · 2012
    UK NEQAS for Molecular Genetics scheme report on GIST molecular testing. Reviews quality assurance rounds for KIT and PDGFRA testing but does not discuss individual intronic variants.
    Does not name this variant
    PMID 22685257 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methods paper describing a classification framework and does not discuss individual KIT variants.
    Does not name this variant
    PMID 28492532 ↗

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

gnomAD v4.1 28 / 1,574,512 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar 1 Likely benign 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

This variant is present in gnomAD v4.1 (AF= 1.77833e-05; MAF= 0.00178%, 28/1574512 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 8.85936e-05; MAF= 0.00886%, 8/90300 alleles, homozygotes = 1); grpmax FAF= 4.401e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 2.79394e-05; MAF= 0.00279%, 7/250542 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 6.53381e-05; MAF= 0.00653%, 2/30610 alleles, homozygotes = 1); grpmax FAF= 1.082e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 415791)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).