chr7-107701928-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7
The NM_000441.2(SLC26A4):c.1905G>A(p.Glu635Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,612,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000441.2 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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SLC26A4 | ENST00000644269.2 | c.1905G>A | p.Glu635Glu | synonymous_variant | Exon 17 of 21 | NM_000441.2 | ENSP00000494017.1 | |||
SLC26A4 | ENST00000492030.2 | n.192G>A | non_coding_transcript_exon_variant | Exon 2 of 6 | 5 | |||||
SLC26A4 | ENST00000644846.1 | n.615G>A | non_coding_transcript_exon_variant | Exon 7 of 10 | ENSP00000494344.1 | |||||
SLC26A4 | ENST00000480841.5 | n.*44G>A | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000111 AC: 28AN: 251196Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135756
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1460672Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15AN XY: 726754
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74468
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
See Variant Classification Assertion Criteria. -
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Pendred syndrome Uncertain:2
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Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1
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not specified Benign:1
Variant summary: SLC26A4 c.1905G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 251196 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00011 vs 0.0035), allowing no conclusion about variant significance. c.1905G>A has been reported in the literature in individuals affected with enlarged vestibular aqueduct/hearing loss without strong evidence for causality (Dai_2008, Yuan_2009, Li_2014, Yuan_2012). These reports do not provide unequivocal conclusions about association of the variant with Pendred Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One lab classified the variant as likely benign while two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at