rs756969021
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS1_SupportingBP4
This summary comes from the ClinGen Evidence Repository: The SLC26A4 p.Ser49Arg variant has been identified in a heterozygous state in two Chinese individuals with congenital non-syndromic hearing loss (PMID:25149764). No information about segregation of the variant or whether it was in trans with another SLC26A4 variant was given. The filtering allele frequency of the p.Ser49Arg variant in the SLC26A4 gene is 0.27% for East Asian chromosomes by gnomAD (44/12282 with 95% CI), which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). Splice prediction analysis using MaxEntScan does not suggest an impact to splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1_Supporting, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA4432373/MONDO:0010134/005
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.147C>G | p.Ser49Arg | missense_variant | 2/21 | ENST00000644269.2 | NP_000432.1 | |
SLC26A4-AS1 | NR_028137.1 | n.11G>C | non_coding_transcript_exon_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.147C>G | p.Ser49Arg | missense_variant | 2/21 | NM_000441.2 | ENSP00000494017 | P1 | ||
SLC26A4-AS1 | ENST00000668981.1 | n.71G>C | non_coding_transcript_exon_variant | 1/2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000290 AC: 41AN: 141150Hom.: 0 AF XY: 0.000288 AC XY: 22AN XY: 76414
GnomAD4 exome AF: 0.0000844 AC: 117AN: 1386612Hom.: 1 Cov.: 30 AF XY: 0.0000921 AC XY: 63AN XY: 684394
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74384
ClinVar
Submissions by phenotype
Pendred syndrome Uncertain:2Benign:3
Likely benign, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Oct 02, 2019 | The SLC26A4 p.Ser49Arg variant has been identified in a heterozygous state in two Chinese individuals with congenital non-syndromic hearing loss (PMID: 25149764). No information about segregation of the variant or whether it was in trans with another SLC26A4 variant was given. The filtering allele frequency of the p.Ser49Arg variant in the SLC26A4 gene is 0.27% for East Asian chromosomes by gnomAD (44/12282 with 95% CI), which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). Splice prediction analysis using MaxEntScan does not suggest an impact to splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1_Supporting, BP4. - |
Benign, no assertion criteria provided | clinical testing | The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine | May 12, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 27, 2021 | NM_000441.1(SLC26A4):c.147C>G(S49R) is a missense variant classified as a variant of uncertain significance in the context of Pendred syndrome. S49R has been observed in cases with relevant disease (PMID: 25372295, 25587757, 28786104, 25830873, 31427586). Functional assessments of this variant are available in the literature (PMID: 31599023). S49R has been observed in population frequency databases (gnomAD: EAS 0.37%). In summary, there is insufficient evidence to classify NM_000441.1(SLC26A4):c.147C>G(S49R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 03, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
other, no assertion criteria provided | clinical testing;in vitro | National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center | Aug 20, 2019 | Benign effect in vitro experiment Benign effect in vitro experiment |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 12, 2022 | Variant summary: SLC26A4 c.147C>G (p.Ser49Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 141150 control chromosomes, predominantly at a frequency of 0.0038 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in SLC26A4 causing Pendred Syndrome phenotype (0.0038 vs 0.0035), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.147C>G has been reported in the literature in heterozygous individuals affected with non-syndromic hearing loss, congenital hypothyroidism, and Pendred Syndrome (e.g. Du_2014, Zhao_2014, Ideura_2019, Zhang_2022), however without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Pendred Syndrome. Functional studies have found the variant has little to no effect on protein expression, membrane localization, and ion transport activity when compared with the wild-type protein (e.g. Wasano_2020, Zhang_2022). Five ClinVar submitters including an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) (evaluation after 2014) cite the variant as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 05, 2015 | p.Ser49Arg in exon 2 of SLC26A4: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, >10 mammals have an Arginine (Arg) at this position. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at