NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant at position -2 in SMARCA4, a gene where loss of function is an established germline disease mechanism causing rhabdoid tumor predisposition syndrome type 2 (RTPS2) and small cell carcinoma of the ovary hypercalcemic type (SCCOHT) [PVS1, very strong].1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency = 0%), consistent with PM2 at moderate strength under generic ACMG/AMP 2015 criteria.2 SpliceAI predicts a strong splice-disrupting effect (max delta = 1.0; DS_AL=1.0, DS_AG=0.89) and BayesDel predicts a damaging score (0.66), but PP3 is not stacked with PVS1 per ClinGen SVI guidance (PMC6185798) to avoid double-counting the same splice-effect evidence.3 This variant is absent from ClinVar and has not been reported in any publication; no external classification, functional data, segregation data, or de novo observations are available.4 Under generic ACMG/AMP 2015 combination rules, one very strong (PVS1) and one moderate (PM2) criterion are sufficient for a Pathogenic classification. However, transcript version discrepancy (NM_001128849.1 vs NM_001128849.3) and absence of RNA-confirmed splicing impact warrant confirmatory review.5
SMARCA4
Final classification
Likely Pathogenic
PVS1PM2
SMARCA4
c.1813-2A>T
p.?
This variant
NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant at position -2 in SMARCA4, a gene where loss of function is an established germline disease mechanism causing rhabdoid tumor predisposition syndrome type 2 (RTPS2) and small cell carcinoma of the ovary hypercalcemic type (SCCOHT) [PVS1, very strong].
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.
Classification rationale
PVS1PM2
Likely Pathogenic
SMARCA4 c.1813-2A>T
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
3
spliceai ↗bayesdelpvs1_generic_framework ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_001128849.1 · variants mapped to exon structure
SMARCA4
NM_001128849.1
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
review
Pathogenic
NM_001128849.1:c.1813-2A>T is a canonical splice acceptor variant (position -2) in SMARCA4, a gene for which loss of function is an established germline disease mechanism causing rhabdoid tumor predisposition syndrome type 2 (RTPS2) and small cell carcinoma of the ovary hypercalcemic type (SCCOHT). Under the ClinGen SVI PVS1 framework (PMC6185798), canonical ±1,2 splice variants are treated as null variants and qualify for PVS1 at very strong strength when the gene LoF disease mechanism is confirmed.
Canonical splice acceptor variant at position -2 (c.1813-2A>T)SMARCA4 loss of function is an established germline disease mechanism for RTPS2 and SCCOHTClinGen SVI PVS1 framework (PMC6185798) assigns null-variant weight to canonical splice variants
✓
PM2
moderate
Pathogenic
NM_001128849.1:c.1813-2A>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), consistent with PM2 under generic ACMG/AMP 2015 criteria (allele frequency <0.1% in population databases).
Absent from gnomAD v2.1 (0 alleles in exomes)Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)
Assessed · not applied
· 3 not met · 15 not assessed
Pathogenic
PS2
No de novo data are available for this variant.
PS3
No well-established in vitro or in vivo functional studies have been identified for NM_001128849.1:c.1813-2A>T.
PS4
No case-control or cohort data are available to assess whether the prevalence of NM_001128849.1:c.1813-2A>T is significantly increased in affected individuals versus controls.
PM1
No mutational hotspot or critical functional domain data are available specifically for the c.1813-2 splice acceptor position in SMARCA4.
PM6
No de novo observation of NM_001128849.1:c.1813-2A>T has been reported.
PP1
No co-segregation data are available for NM_001128849.1:c.1813-2A>T with disease in multiple affected family members.
PP2
PP2 applies to missense variants in genes where missense variants are a common disease mechanism and benign missense variation is rare.
PP4
No patient phenotype or clinical history is available for NM_001128849.1:c.1813-2A>T.
PP5
No reputable source has reported NM_001128849.1:c.1813-2A>T as pathogenic.
Benign
BA1
NM_001128849.1:c.1813-2A>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
NM_001128849.1:c.1813-2A>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No data are available regarding observation of NM_001128849.1:c.1813-2A>T in healthy adults with full penetrance expected at an early age.
BS3
No well-established functional studies have been performed for NM_001128849.1:c.1813-2A>T demonstrating no deleterious effect on splicing or protein function.
BS4
No segregation data are available to assess whether NM_001128849.1:c.1813-2A>T lacks segregation with disease in affected family members.
BP2
No data are available regarding observation of NM_001128849.1:c.1813-2A>T in trans with a known pathogenic variant in SMARCA4.
BP4
In silico predictions are consistent with a deleterious effect.
BP5
No case has been reported where NM_001128849.1:c.1813-2A>T is found in an individual with an alternative molecular basis for disease.
BP6
No reputable source has reported NM_001128849.1:c.1813-2A>T as benign or likely benign.
N/A · 5
PS1 · PM5 · PP3 · BP1 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.66.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links