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RNF43c.252+2C>GLikely pathogenic
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Variant interpretation report

RNF43 c.252+2C>G, p.?

NM_017763.5:c.252+2C>G NP_060233.3:p.? View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

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

In plain language

Gene-level background from the recorded interpretation.

About RNF43

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

NM_017763.5:c.252+2C>G is a canonical splice donor variant at the +2 position of intron 2 in RNF43, a gene where loss of function is an established germline disease mechanism (serrated polyposis syndrome, colorectal cancer predisposition). Assessed under ClinGen SVI PVS1 recommendations (PMC6185798) as a null variant in a gene with confirmed LOF disease mechanism. SpliceAI predicts no significant splice impact (max delta = 0.0), which conflicts with the canonical splice site expectation; RNA functional studies are recommended to confirm the splicing effect.

PM2Moderate
PM2 · moderate

Extremely rare in population databases. gnomAD v2.1 allele frequency = 3.98e-06 (1/251,184 alleles, 0 homozygotes). gnomAD v4.1 allele frequency = 6.20e-07 (1/1,613,886 alleles, 0 homozygotes). Absent from gnomAD-Canada. Allele frequency is well below the 0.1% PM2 threshold.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely 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, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely 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 / 1,613,886 alleles

gnomAD v4.1: 1 / 1,613,886 alleles. Recorded AF 6.19622e-07. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98115e-06; MAF= 0.00040%, 1/251184 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80685e-06; MAF= 0.00088%, 1/113548 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance.

Context only ClinVar ↗
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
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV109424238, n = 1 times).

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: 2 met · 6 not met · 11 not assessed · 10 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_017763.5:c.252+2C>G is a canonical splice donor variant at the +2 position of intron 2 in RNF43, a gene where loss of function is an established mechanism for germline disease including serrated polyposis syndrome and colorectal cancer predisposition. Assessed under ClinGen SVI PVS1 recommendations (PMC6185798) as a null variant (PVS1).

The variant is extremely rare in population databases, with an allele frequency of 3.98e-06 in gnomAD v2.1 (1/251,184 alleles, 0 homozygotes) and 6.20e-07 in gnomAD v4.1 (1/1,613,886 alleles, 0 homozygotes), and is absent from gnomAD-Canada. Allele frequency is well below the 0.1% PM2 threshold (PM2).

ClinVar reports this variant as Uncertain significance (2 clinical laboratories, criteria provided, single submitter; Variation ID 3669600). No variant-specific functional studies, segregation data, or de novo observations were identified in the reviewed literature.

SpliceAI predicts no significant splice impact (max delta = 0.0), which conflicts with the canonical splice site expectation. This discrepancy may reflect SpliceAI calibration for a non-canonical reference donor (C at +2 instead of the consensus T). RNA functional studies are recommended to resolve this conflict.

Under ACMG/AMP 2015 generic classification rules, 1 Very Strong (PVS1) + 1 Moderate (PM2) supports a classification of Likely Pathogenic. However, the SpliceAI conflict warrants caution and human review.

Met · 2

PVS1 Very strongNM_017763.5:c.252+2C>G is a canonical splice donor variant at the +2 position of intron 2 in RNF43, a gene where loss of function is an established germline disease mechanism (serrated polyposis syndrome, colorectal cancer predisposition). Assessed under ClinGen SVI PVS1 recommendations (PMC6185798) as a null variant in a gene with confirmed LOF disease mechanism. SpliceAI predicts no significant splice impact (max delta = 0.0), which conflicts with the canonical splice site expectation; RNA functional studies are recommended to confirm the splicing effect. Details ▾Hide ▴
Evidence considered
  • Canonical +2 splice donor variant (c.252+2C>G) in intron 2 of RNF43
  • RNF43 loss of function is an established germline disease mechanism (serrated polyposis syndrome
  • colorectal cancer)
  • Assessed under ClinGen SVI PVS1 recommendations (PMC6185798)
Still missing
  • SpliceAI max delta = 0.0 conflicts with canonical splice site expectation
  • RNA studies needed to confirm splicing effect
  • No confirmation of transcript relevance for NM_017763.5 (refseq_select
  • not MANE select)
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM2 ModerateExtremely rare in population databases. gnomAD v2.1 allele frequency = 3.98e-06 (1/251,184 alleles, 0 homozygotes). gnomAD v4.1 allele frequency = 6.20e-07 (1/1,613,886 alleles, 0 homozygotes). Absent from gnomAD-Canada. Allele frequency is well below the 0.1% PM2 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF = 3.98e-06 (1/251
  • 184 alleles
  • 0 homozygotes)
  • gnomAD v4.1 AF = 6.20e-07 (1/1
  • 613
  • 886 alleles
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 6 · evaluated, threshold not reached

PP3 SpliceAI max delta = 0.0 (no significant splice impact predicted). BayesDel score = 0.65 (equivocal). Additionally, per PMC6185798 guidance, PP3 should not be stacked with PVS1 for the same splice-effect prediction evidence when PVS1 is applied for a canonical splice variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.00 (no splice impact predicted)
  • BayesDel score = 0.65 (equivocal
  • not clearly damaging)
  • PP3 double-counting prohibition with PVS1 per PMC6185798
Sources
spliceai ↗bayesdel
PP5 ClinVar classification is Uncertain significance (2 clinical laboratories, criteria provided, single submitter). The variant has not been reported as pathogenic or likely pathogenic by a reputable source. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 3669600: Uncertain significance
  • 2 clinical laboratories
  • criteria provided
  • single submitter
Sources
clinvar ↗
BA1 gnomAD allele frequency (v2.1: 3.98e-06; v4.1: 6.20e-07) is far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF = 3.98e-06
  • v4.1 AF = 6.20e-07
  • both << 1%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 gnomAD allele frequency (v2.1: 3.98e-06; v4.1: 6.20e-07) is far below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF = 3.98e-06
  • v4.1 AF = 6.20e-07
  • both << 0.3%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SpliceAI predicts no splice impact (max delta = 0.0), but this is insufficient to support a benign interpretation given the canonical splice site position. SpliceAI may not be well-calibrated for non-canonical reference donor sequences. BayesDel score of 0.65 is equivocal. Multiple lines of in silico evidence do not convincingly predict a benign effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no splice impact predicted
  • but uncertain calibration for non-canonical donor)
  • BayesDel score = 0.65 (equivocal
  • not clearly benign)
Sources
spliceai ↗bayesdel
BP6 ClinVar reports Uncertain significance, not benign or likely benign. BP6 requires classification as benign by a reputable source. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 3669600: Uncertain significance only
  • no benign classification from reputable source
Sources
clinvar ↗

Not assessed · 11 · no assessment recorded

PS2 No de novo observation data available for this variant in any reviewed source. Details ▾Hide ▴
Still missing
  • No de novo testing or reporting identified
PS3 No variant-specific functional studies identified. The ClinVar-submitted PMIDs (17576681, 9536098) are general splicing methodology papers that do not mention NM_017763.5:c.252+2C>G. Details ▾Hide ▴
Still missing
  • No variant-specific functional assays (RNA studies
  • minigene splicing assays) identified
PS4 No case-control or prevalence data comparing affected individuals to controls available for this variant. Details ▾Hide ▴
Still missing
  • No case-control or cohort prevalence data identified
PM6 No de novo observation data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing or reporting identified
PP1 No cosegregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation studies identified
PP4 No phenotype specificity data available for affected individuals carrying this variant. Details ▾Hide ▴
Still missing
  • No patient phenotype data identified
BS2 No data on observation in healthy adults available. Details ▾Hide ▴
Still missing
  • No healthy adult carrier data identified
BS3 No variant-specific functional studies demonstrating no deleterious effect were identified. Details ▾Hide ▴
Still missing
  • No functional studies (RNA
  • protein) demonstrating no damaging effect
BS4 No non-segregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation or non-segregation data identified
BP2 No data on observation in trans with a pathogenic variant available. Details ▾Hide ▴
Still missing
  • No in trans observation data identified
BP5 No data on alternate molecular basis for disease in cases carrying this variant. Details ▾Hide ▴
Still missing
  • No alternate molecular basis data identified
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ASplice variant does not result in an amino acid substitution; same amino acid change from a different nucleotide change is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM1 N/ASplice variant located in intron 2, outside coding sequence. No mutational hotspot or critical functional domain directly affected by an amino acid substitution at this position. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ANo recessive inheritance context established; PM3 requires observation in trans with a pathogenic variant for recessive disorders. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASplice variant does not alter protein length via non-repeat in-frame indel; PM4 applies to non-repeat in-frame insertions/deletions or stop-loss variants. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo residue context for same-position comparator evaluation; splice variant does not produce a defined amino acid change for residue-level comparison. Details ▾Hide ▴

No further detail was recorded.

PP2 N/ASplice variant, not a missense change; PP2 applies only to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ASplice variant, not a missense change; BP1 applies to missense variants in genes where truncating variants are the primary pathogenic mechanism. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASplice variant does not produce an in-frame insertion/deletion; BP3 applies to in-frame indels in repetitive regions without known function. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANot a synonymous variant; c.252+2C>G is an intronic splice donor variant. BP7 applies to synonymous variants with no predicted splice effect. Details ▾Hide ▴

No further detail was recorded.

PS5 N/ANot a missense variant; same-residue pathogenic comparator evaluation is not applicable for a splice variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
RNF43
Transcript
NM_017763.5
Coding (HGVS c.)
NM_017763.5:c.252+2C>G
Protein (HGVS p.)
NP_060233.3:p.?
GRCh38
chr17:58415324 G>C
GRCh37
chr17:56492685 G>C
ClinVar
3669600
COSMIC
COSV109424238

Gene diagram

Every interpreted variant in RNF43, mapped onto the exon structure of NM_017763.5. Select a row to find it on the plot.

RNF43NM_017763.5
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,613,886 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 1 / 251,184 alleles AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,613,886 alleles · 0 hom
European (non-Finnish)1 / 1,179,848 8.5e-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.

gnomAD v2.1

AF 4e-06 · 1 / 251,184 alleles · 0 hom
European (non-Finnish)1 / 113,548 8.8e-06
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19622e-07; MAF= 0.00006%, 1/1613886 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47567e-07; MAF= 0.00008%, 1/1179848 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98115e-06; MAF= 0.00040%, 1/251184 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80685e-06; MAF= 0.00088%, 1/113548 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +142 bp
0.000
SpliceAI acceptor gainat +37 bp
0.000
SpliceAI donor lossat +62 bp
0.000
SpliceAI donor gainat +426 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
0.650

How the predictions were used

PP3 SpliceAI max delta = 0.0 (no significant splice impact predicted). BayesDel score = 0.65 (equivocal). Additionally, per PMC6185798 guidance, PP3 should not be stacked with PVS1 for the same splice-effect prediction evidence when PVS1 is applied for a canonical splice variant. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.00 (no splice impact predicted)
  • BayesDel score = 0.65 (equivocal
  • not clearly damaging)
  • PP3 double-counting prohibition with PVS1 per PMC6185798
Sources
spliceai ↗bayesdel
BP4 SpliceAI predicts no splice impact (max delta = 0.0), but this is insufficient to support a benign interpretation given the canonical splice site position. SpliceAI may not be well-calibrated for non-canonical reference donor sequences. BayesDel score of 0.65 is equivocal. Multiple lines of in silico evidence do not convincingly predict a benign effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.00 (no splice impact predicted
  • but uncertain calibration for non-canonical donor)
  • BayesDel score = 0.65 (equivocal
  • not clearly benign)
Sources
spliceai ↗bayesdel
BP7 N/ANot a synonymous variant; c.252+2C>G is an intronic splice donor variant. BP7 applies to synonymous variants with no predicted splice effect. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.65.

2 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

  • Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.
    Buratti E et al. · 2007
    Comprehensive compilation and analysis of 346 aberrant 5' splice sites from 166 human disease genes. Compares computational tools for splice site prediction and examines mutation patterns and nucleotide structure at donor splice sites. NM_017763.5:c.252+2C>G was not identified in this paper.
    Does not name this variant
    PMID 17576681 ↗
  • Statistical features of human exons and their flanking regions.
    Zhang MQ · 1998
    Statistical survey of human exon features and flanking genomic DNA sequences, classifying exons into 12 categories with nucleotide composition analysis. Provides baseline statistical models of splice site regions. NM_017763.5:c.252+2C>G was not identified in this paper.
    Does not name this variant
    PMID 9536098 ↗

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

gnomAD v4.1 1 / 1,613,886 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 2 Uncertain significance 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= 6.19622e-07; MAF= 0.00006%, 1/1613886 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47567e-07; MAF= 0.00008%, 1/1179848 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98115e-06; MAF= 0.00040%, 1/251184 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.80685e-06; MAF= 0.00088%, 1/113548 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 3669600)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.65.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV109424238, n = 1 times).