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

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000084 ( 1 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

19

Clinical Significance

Likely benign reviewed by expert panel U:4B:6O:1

Conservation

PhyloP100: -0.0920
Variant links:
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)

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC26A4NM_000441.2 linkuse as main transcriptc.147C>G p.Ser49Arg missense_variant 2/21 ENST00000644269.2 NP_000432.1
SLC26A4-AS1NR_028137.1 linkuse as main transcriptn.11G>C non_coding_transcript_exon_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC26A4ENST00000644269.2 linkuse as main transcriptc.147C>G p.Ser49Arg missense_variant 2/21 NM_000441.2 ENSP00000494017 P1O43511-1
SLC26A4-AS1ENST00000668981.1 linkuse as main transcriptn.71G>C non_coding_transcript_exon_variant 1/2

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152230
Hom.:
0
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.000290
AC:
41
AN:
141150
Hom.:
0
AF XY:
0.000288
AC XY:
22
AN XY:
76414
show subpopulations
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 SAS exome
AF:
0.00
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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00316
Gnomad4 SAS exome
AF:
0.0000253
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000346
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152230
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74384
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00154
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
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:4Benign:6Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Pendred syndrome Uncertain:2Benign:3
Likely benign, reviewed by expert panelcurationClinGen Hearing Loss Variant Curation Expert PanelOct 02, 2019The 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 providedclinical testingThe Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of MedicineMay 12, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 submitterclinical testingMyriad Genetics, Inc.Oct 27, 2021NM_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 providedclinical testingNatera, Inc.Sep 16, 2020- -
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 03, 2016- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1Other:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 providedclinical testing;in vitroNational Institute of Sensory Organs, National Hospital Organization Tokyo Medical CenterAug 20, 2019Benign effect in vitro experiment Benign effect in vitro experiment
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 12, 2022Variant 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 submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 05, 2015p.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: dbNSFP v4.3

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;T;T
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.61
FATHMM_MKL
Benign
0.68
D
LIST_S2
Benign
0.52
.;T;T
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.0080
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.81
N;N;.
MutationTaster
Benign
0.96
N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
0.78
N;.;N
REVEL
Benign
0.11
Sift
Benign
0.85
T;.;T
Sift4G
Benign
1.0
T;.;T
Polyphen
0.0
B;B;.
Vest4
0.15
MutPred
0.33
Loss of phosphorylation at S49 (P = 0.0157);Loss of phosphorylation at S49 (P = 0.0157);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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs756969021; hg19: chr7-107302233; API