chr7-103413015-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_198999.3(SLC26A5):c.390A>C(p.Arg130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC26A5
NM_198999.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.188

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: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

PP5

Variant 7-103413015-T-G is Pathogenic according to our data. Variant chr7-103413015-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 97020.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A5	NM_198999.3 link	c.390A>C	p.Arg130Ser	missense_variant	Exon 5 of 20	ENST00000306312.8	NP_945350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC26A5	ENST00000306312.8 link	c.390A>C	p.Arg130Ser	missense_variant	Exon 5 of 20	1	NM_198999.3	ENSP00000304783.3
SLC26A5	ENST00000393727.5 link	c.390A>C	p.Arg130Ser	missense_variant	Exon 3 of 18	1		ENSP00000377328.1
SLC26A5	ENST00000393723.2 link	c.390A>C	p.Arg130Ser	missense_variant	Exon 3 of 17	1		ENSP00000377324.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454312

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723972

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33294

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.00

AC:

AN:

86112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1105148

Other (OTH)

AF:

0.00

AC:

AN:

60164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 61

Pathogenic:1

Oct 28, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

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

Eigen

Benign

0.16

Eigen_PC

Benign

0.098

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

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

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.88

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

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

3.0

M;M;M;M;M;M;.;.;M

PhyloP100

0.19

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-4.9

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

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

0.53

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

Vest4

0.63

MutPred

0.77

Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);

MVP

0.86

MPC

0.23

ClinPred

0.99

GERP RS

0.31

Varity_R

0.81

gMVP

0.79

Mutation Taster

=0/100

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over