NM_000441.2:c.147C>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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

Clinical Significance

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

Conservation

PhyloP100: -0.0920

Publications

13 publications found

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 links:

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

SLC26A4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Sel.	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	O43511-1
	SLC26A4-AS1	NR_028137.1		n.11G>C		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

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	O43511-1
SLC26A4	ENST00000888701.1		c.147C>G	p.Ser49Arg	missense	Exon 1 of 20	ENSP00000558760.1
SLC26A4	ENST00000888700.1		c.147C>G	p.Ser49Arg	missense	Exon 2 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152230

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000290

AC:

AN:

141150

AF XY:

0.000288

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 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.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

684394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31592

American (AMR)

AF:

0.00

AC:

AN:

35720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25148

East Asian (EAS)

AF:

0.00316

AC:

113

AN:

35792

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4886

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078990

Other (OTH)

AF:

0.0000346

AC:

AN:

57832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00154

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.000129

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pendred syndrome (5)

not provided (2)

not specified (2)

Autosomal recessive nonsyndromic hearing loss 4 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.068

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.52

M_CAP

Benign

0.025

MetaRNN

Benign

0.0080

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.81

PhyloP100

-0.092

PrimateAI

Benign

0.36

PROVEAN

Benign

0.78

REVEL

Benign

0.11

Sift

Benign

0.85

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.15

MutPred

0.33

Loss of phosphorylation at S49 (P = 0.0157)

MVP

0.73

MPC

0.011

ClinPred

0.058

GERP RS

-0.31

Varity_R

0.11

gMVP

0.52

Mutation Taster

=77/23

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over