rs756969021

Variant names:

• chr7-107661788-C-G
• rs756969021
• NM_000441.2:c.147C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-107661788-C-G
• chr7-107661788-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BS1_Supporting BP4

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:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (1 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:6 O:1
• Conservation: PhyloP100: -0.0920
• Publications: 13 publications found

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

SLC26A4-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000441.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.147C>G	p.Ser49Arg	missense	Exon 2 of 21	NP_000432.1
	SLC26A4-AS1	NR_028137.1		n.11G>C		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.147C>G	p.Ser49Arg	missense	Exon 2 of 21	ENSP00000494017.1
	SLC26A4	ENST00000440056.1	TSL:4	c.147C>G	p.Ser49Arg	missense	Exon 2 of 4	ENSP00000394760.1
	SLC26A4-AS1	ENST00000440512.4	TSL:3	n.216G>C		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000290 AC: 41 AN: 141150 AF XY: 0.000288

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00382

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000844 AC: 117 AN: 1386612 Hom.: 1 Cov.: 30 AF XY: 0.0000921 AC XY: 63 AN XY: 684394

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25148

East Asian (EAS) AF: 0.00316 AC: 113 AN: 35792

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4886

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078990

Other (OTH) AF: 0.0000346 AC: 2 AN: 57832

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.000129 AC: 12

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4 Benign:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Pendred syndrome Uncertain:2 Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 27, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 16, 2025

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000441.2(SLC26A4):c.147C>G (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 c.147C>G variant in the SLC26A4 gene is 0.27% for East Asian chromosomes by gnomADv4 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 and splice prediction analysis using MaxEntScan does not suggest an impact to splicing (BP4). Fluorescence HCO3−/Cl− and I−/Cl− antiport functional assay show no difference compared to wild type protein (PMID : 31599023 ; BS3_P). 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, BS3_Supporting, BP4 (ClinGen Hearing Loss VCEP specifications version 2; 7/16/2025).

May 12, 2020

The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Uncertain:1 Benign:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 03, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1 Other:1

Aug 20, 2019

National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center

Significance: other

Review Status: no assertion criteria provided

Collection Method: clinical testing;in vitro

Benign effect in vitro experiment Benign effect in vitro experiment

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not specified Benign:2

Nov 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 12, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.092
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.78	N
REVEL	Benign	0.11
Sift	Benign	0.85	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.33		Loss of phosphorylation at S49 (P = 0.0157)
MVP		0.73
MPC		0.011
ClinPred		0.058	T
GERP RS		-0.31
Varity_R		0.11
gMVP		0.52
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs756969021; hg19: chr7-107302233;