rs117444825

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198999.3(SLC26A5):c.989A>G(p.Asn330Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,613,928 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0095 ( 9 hom., cov: 32)

Exomes 𝑓: 0.017 ( 253 hom. )

Consequence

SLC26A5
NM_198999.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.24

Publications

9 publications found

Variant links:

Genes affected

SLC26A5 (HGNC:9359): (solute carrier family 26 member 5) This gene encodes a member of the SLC26A/SulP transporter family. The protein functions as a molecular motor in motile outer hair cells (OHCs) of the cochlea, inducing changes in cell length that act to amplify sound levels. The transmembrane protein is an incomplete anion transporter, and does not allow anions to cross the cell membrane but instead undergoes a conformational change in response to changes in intracellular Cl- levels that results in a change in cell length. The protein functions at microsecond rates, which is several orders of magnitude faster than conventional molecular motor proteins. Mutations in this gene are potential candidates for causing neurosensory deafness. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

SLC26A5 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 61
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

SLC26A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0103934705).

BP6

Variant 7-103393049-T-C is Benign according to our data. Variant chr7-103393049-T-C is described in ClinVar as Benign. ClinVar VariationId is 48341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00948 (1444/152280) while in subpopulation NFE AF = 0.0169 (1148/68018). AF 95% confidence interval is 0.0161. There are 9 homozygotes in GnomAd4. There are 653 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A5	NM_198999.3 link	c.989A>G	p.Asn330Ser	missense_variant	Exon 10 of 20	ENST00000306312.8	NP_945350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC26A5	ENST00000306312.8 link	c.989A>G	p.Asn330Ser	missense_variant	Exon 10 of 20	1	NM_198999.3	ENSP00000304783.3
SLC26A5	ENST00000393727.5 link	c.989A>G	p.Asn330Ser	missense_variant	Exon 8 of 18	1		ENSP00000377328.1
SLC26A5	ENST00000393723.2 link	c.989A>G	p.Asn330Ser	missense_variant	Exon 8 of 17	1		ENSP00000377324.1

Frequencies

GnomAD3 genomes

AF:

0.00949

AC:

1444

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00287

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00895

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0169

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00978

AC:

2457

AN:

251122

AF XY:

0.00960

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00961

Gnomad NFE exome

AF:

0.0182

Gnomad OTH exome

AF:

0.00848

GnomAD4 exome

AF:

0.0169

AC:

24638

AN:

1461648

Hom.:

253

Cov.:

AF XY:

0.0161

AC XY:

11677

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.00284

AC:

AN:

33470

American (AMR)

AF:

0.00215

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000995

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0105

AC:

559

AN:

53420

Middle Eastern (MID)

AF:

0.00712

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0207

AC:

23064

AN:

1111832

Other (OTH)

AF:

0.0124

AC:

748

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1336

2673

4009

5346

6682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

890

1780

2670

3560

4450

<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:

0.00948

AC:

1444

AN:

152280

Hom.:

Cov.:

AF XY:

0.00877

AC XY:

653

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00286

AC:

119

AN:

41548

American (AMR)

AF:

0.00268

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00895

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0169

AC:

1148

AN:

68018

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

144

216

288

360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0144

Hom.:

Bravo

AF:

0.00894

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0169

AC:

145

ExAC

AF:

0.0108

AC:

1313

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0153

EpiControl

AF:

0.0151

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 20, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 13, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Asn330Ser in Exon 10 of SLC26A5: This variant is not expected to have clinical s ignificance because it has been identified in 1.7% (121/7020) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs117444825). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 61

Benign:1

Aug 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

.;.;.;T;.;T;.;T;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.96

D;D;.;D;D;D;D;.;D

MetaRNN

Benign

0.010

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

-0.26

N;N;N;N;N;.;.;.;N

PhyloP100

2.2

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.83

N;N;N;N;N;.;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.068

T;T;T;T;T;.;T;T;T

Sift4G

Benign

0.13

T;T;T;T;T;T;T;T;T

Polyphen

0.10

B;B;.;B;.;.;.;.;.

Vest4

0.14

MPC

0.19

ClinPred

0.013

GERP RS

3.2

Varity_R

0.049

gMVP

0.40

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over