rs141952919

Positions:

chr7-103421378-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A5	NM_198999.3 linkuse as main transcript	c.137T>C	p.Leu46Pro	missense_variant	3/20	ENST00000306312.8	NP_945350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A5	ENST00000306312.8 linkuse as main transcript	c.137T>C	p.Leu46Pro	missense_variant	3/20	1	NM_198999.3	ENSP00000304783	P4	P58743-1

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

GnomAD3 exomes

AF:

0.00312

AC:

785

AN:

251314

Hom.:

AF XY:

0.00319

AC XY:

433

AN XY:

135826

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 SAS exome

AF:

0.00268

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

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.00398

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00255

Gnomad4 FIN exome

AF:

0.00144

Gnomad4 NFE exome

AF:

0.00519

Gnomad4 OTH exome

AF:

0.00318

GnomAD4 genome

AF:

0.00265

AC:

403

AN:

152334

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00476

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00418

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	SLC26A5: PP3, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2021

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

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 25, 2023

- -

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

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

MutationTaster

Benign

1.0

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

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

Varity_R

0.87

gMVP

0.91

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over