LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-01
Case ID: NM_000441.2_c.919-2A_G_20261101_151539
Framework: ACMG/AMP 2015
Variant classification summary

NM_000441.2:c.919-2A>G

SLC26A4  · NP_000432.1:p.?  · NM_000441.2
GRCh37: chr7:107323898 A>G  ·  GRCh38: chr7:107683453 A>G
Gene: SLC26A4 Transcript: NM_000441.2
Final call
VUS
PVS1 very strong PM3 moderate PP1 supporting PP5 supporting BA1 stand-alone benign BS1 strong
All criteria require review: For research and educational purposes only.
Variant details
Gene
SLC26A4
Transcript
NM_000441.2
Protein
NP_000432.1:p.?
gnomAD AF
7.745914185185598e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 very strong: exact-variant RT-PCR showed complete exon 8 skipping with a frameshift and premature termination.
2
PM3 moderate: affected patients carried the variant in trans with pathogenic p.H723R.
3
PP1 supporting: the variant segregated with hearing loss in affected relatives.
4
PP5 supporting: an expert-panel classification recorded the variant as pathogenic.
5
BA1 stand-alone benign: gnomAD v2.1 East Asian allele frequency was 0.00506367, above the 0.005 threshold.
6
BS1 strong: gnomAD v2.1 East Asian allele frequency was 0.00506367, above the 0.003 threshold.
Final determination: Under the VCEP's ACMG/AMP 2015 base rules, the applied criteria satisfy both a pathogenic rule and a benign rule, so the conflicting evidence yields a VUS.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 Met Met at very strong: exact-variant RT-PCR showed complete exon 8 skipping, causing an 83-nucleotide frameshift and premature termination in SLC26A4.
cspec pvs1_gene_context pvs1_variant_assessment PMID:15574297 PMID:24007330
PS1 Not assessed Not assessed: no different pathogenic substitution at c.919-2 with a comparable splice-impact prediction is available for this canonical splice variant.
cspec
PS2 Not met Not met: no proven or assumed de novo occurrence is documented; reported cases show familial transmission in affected relatives.
cspec PMID:10874637 PMID:11502831 PMID:16711435
PS3 Not assessed Not assessed: RNA studies show exon 8 skipping and only 6–17% normal transcript, but the VCEP specifies SLC26A4 radio-isotope or fluorescence assays for PS3.
cspec PMID:15574297 PMID:24007330
PS4 Not assessed Not assessed: the available affected-cohort data report c.919-2A>G in 24% of 111 biallelic cases but provide no matched controls or case-control statistical test.
cspec PMID:24007330
PM1 N/A Not applicable: the VCEP PM1 specification covers only KCNQ4 missense variants at amino acids 271-292, not SLC26A4 c.919-2A>G.
cspec
PM2 Not met Not met: gnomAD v4.1 total AF 0.0000774591 exceeds the VCEP autosomal-recessive PM2 cutoff of 0.00007 (0.007%).
cspec gnomad_v2 gnomad_v4
PM3 Met Met at Moderate strength: affected patients had compound-heterozygous p.H723R/c.919-2A>G genotypes, documenting the target allele in trans with the disease allele.
cspec PMID:24007330
PM4 N/A Not applicable: this is a splice-site substitution, whereas PM4 requires an in-frame insertion or deletion causing a protein length change.
cspec pvs1_variant_assessment
PM5 N/A Not applicable: PM5 requires a missense codon comparison, but c.919-2A>G is a canonical splice variant with protein consequence p.?.
cspec pm5_candidates
PM6 Not met Not met: no affected proband has an unproven but assumed de novo occurrence; available reports describe familial segregation.
cspec PMID:10874637 PMID:11502831 PMID:16711435
PP1 Met Met supporting: the splice-site variant segregates with hearing loss in affected relatives, satisfying the VCEP threshold of one affected relative for recessive disease.
cspec PMID:10874637 PMID:11502831 PMID:16711435
PP2 N/A Not applicable: the VCEP excludes PP2 for this gene.
cspec
PP3 Not assessed Not assessed: SpliceAI max delta 0.998 is not the VCEP-named MaxEntScan result, and PP3 is excluded for canonical -2 variants if PVS1 is used.
cspec spliceai
PP4 Not assessed Not assessed: PP4 requires VCEP Table 7 phenotype-specificity specifications, but those specifications and a complete patient phenotype are unavailable.
cspec
PP5 Met Not applicable: this VCEP explicitly prohibits PP5, regardless of pathogenic reports for c.919-2A>G.
cspec clinvar
BA1 Met Met: gnomAD v2.1 East Asian AF 0.00506367 exceeds the VCEP autosomal-recessive BA1 threshold of 0.005 (0.5%).
cspec gnomad_v2 gnomad_v4
BS1 Met Met strong: gnomAD v2.1 East Asian AF 0.00506367 exceeds the VCEP autosomal-recessive BS1 Strong threshold of 0.003 (0.3%).
cspec gnomad_v2 gnomad_v4
BS2 Not met Not met: gnomAD v2.1 and v4.1 each report 0 homozygotes, with no qualifying biallelic control observation available.
cspec gnomad_v2 gnomad_v4
BS3 Not assessed Not assessed: available RNA studies show abnormal splicing, while no VCEP-specified SLC26A4 assay reports iodide efflux or fluorescence comparable to wild type.
cspec PMID:15574297 PMID:24007330
BS4 Not met Not met: no affected relative lacks the variant and unaffected parents are compatible with expected recessive carrier status, not non-segregation.
cspec PMID:10874637 PMID:11502831 PMID:16711435
BP1 N/A Not applicable: the VCEP excludes BP1 for this gene.
cspec
BP2 Not assessed Not assessed: no qualifying observation of c.919-2A>G in trans with a dominant variant or in cis with a pathogenic variant is documented.
cspec PMID:24007330 PMID:15574297
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region without known function, but this variant is a canonical splice-site substitution.
cspec pvs1_variant_assessment
BP4 Not assessed Not assessed: REVEL is unavailable and no MaxEntScan result establishes no splice impact; SpliceAI max delta 0.998 is not the VCEP-named predictor.
cspec spliceai
BP5 N/A Not applicable: the VCEP expressly says not to use BP5 for autosomal-recessive SLC26A4 because carrier status can coexist with another cause.
cspec
BP6 N/A Not applicable: this VCEP explicitly prohibits BP6, regardless of benign reports from reputable sources.
cspec
BP7 N/A Not applicable: NM_000441.2:c.919-2A>G is a canonical intronic splice-site variant, not a silent variant required by the VCEP BP7 rule.
cspec
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