rs141952919

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.137T>C(p.Leu46Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00424 in 1,614,138 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 26 hom. )

Consequence

SLC26A5
NM_198999.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 6.17

Publications

10 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=0.028838605).

BP6

Variant 7-103421378-A-G is Benign according to our data. Variant chr7-103421378-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165272.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 = 0.00265 (403/152334) while in subpopulation NFE AF = 0.00476 (324/68024). AF 95% confidence interval is 0.00434. There are 3 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A5	NM_198999.3 link	c.137T>C	p.Leu46Pro	missense_variant	Exon 3 of 20	ENST00000306312.8	NP_945350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC26A5	ENST00000306312.8 link	c.137T>C	p.Leu46Pro	missense_variant	Exon 3 of 20	1	NM_198999.3	ENSP00000304783.3
SLC26A5	ENST00000393727.5 link	c.137T>C	p.Leu46Pro	missense_variant	Exon 1 of 18	1		ENSP00000377328.1
SLC26A5	ENST00000393723.2 link	c.137T>C	p.Leu46Pro	missense_variant	Exon 1 of 17	1		ENSP00000377324.1

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

403

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00476

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00312

AC:

785

AN:

251314

AF XY:

0.00319

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000832

Gnomad NFE exome

AF:

0.00502

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00440

AC:

6436

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

3179

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.000984

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00398

AC:

104

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00255

AC:

220

AN:

86252

European-Finnish (FIN)

AF:

0.00144

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00519

AC:

5776

AN:

1111958

Other (OTH)

AF:

0.00318

AC:

192

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

344

688

1032

1376

1720

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<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:

0.00265

AC:

403

AN:

152334

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000842

AC:

AN:

41590

American (AMR)

AF:

0.000785

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00103

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00476

AC:

324

AN:

68024

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00407

Hom.:

Bravo

AF:

0.00255

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00325

AC:

395

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00524

EpiControl

AF:

0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 14, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC26A5: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Feb 22, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu46Pro in Exon 03 of SLC26A5: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (34/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs141952919). -

SLC26A5-related disorder

Benign:1

Sep 17, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive nonsyndromic hearing loss 61

Benign:1

Sep 25, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

.;.;.;.;D;.;T;.;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

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

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.029

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

MetaSVM

Uncertain

0.68

MutationAssessor

Benign

1.7

L;L;L;L;L;L;.;.;.;L

PhyloP100

6.2

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.8

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

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0040

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

Sift4G

Uncertain

0.0070

D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;.;P;.;.;.;.;.

Vest4

0.65

MVP

0.96

MPC

0.69

ClinPred

0.030

GERP RS

5.4

PromoterAI

0.041

Neutral

(source)

Varity_R

0.87

gMVP

0.91

Mutation Taster

=287/13

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

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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