rs17154353

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM5PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000441.2(SLC26A4):c.2218G>A(p.Gly740Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00273 in 1,604,892 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G740V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.014 ( 40 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 43 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 5.59

Publications

17 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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
Pendred syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
athyreosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
thyroid hypoplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC26A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-107710183-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43545.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 4, Pendred syndrome, athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029495358).

BP6

Variant 7-107710182-G-A is Benign according to our data. Variant chr7-107710182-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2182/152248) while in subpopulation AFR AF = 0.0497 (2066/41528). AF 95% confidence interval is 0.048. There are 40 homozygotes in GnomAd4. There are 1041 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.2218G>A	p.Gly740Ser	missense_variant	Exon 19 of 21	ENST00000644269.2	NP_000432.1	O43511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC26A4	ENST00000644269.2 link	c.2218G>A	p.Gly740Ser	missense_variant	Exon 19 of 21		NM_000441.2	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000492030.2 link	n.404G>A		non_coding_transcript_exon_variant	Exon 4 of 6	5
SLC26A4	ENST00000644846.1 link	n.*120G>A		non_coding_transcript_exon_variant	Exon 8 of 10			ENSP00000494344.1	A0A2R8Y4W7
SLC26A4	ENST00000644846.1 link	n.*120G>A		3_prime_UTR_variant	Exon 8 of 10			ENSP00000494344.1	A0A2R8Y4W7

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2182

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0499

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00955

GnomAD2 exomes

AF:

0.00369

AC:

928

AN:

251264

AF XY:

0.00281

show subpopulations

Gnomad AFR exome

AF:

0.0500

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00151

AC:

2194

AN:

1452644

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

932

AN XY:

723258

show subpopulations

African (AFR)

AF:

0.0495

AC:

1643

AN:

33164

American (AMR)

AF:

0.00217

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.000186

AC:

AN:

86042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00365

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000175

AC:

193

AN:

1103800

Other (OTH)

AF:

0.00373

AC:

224

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

101

202

302

403

504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.0143

AC:

2182

AN:

152248

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1041

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0497

AC:

2066

AN:

41528

American (AMR)

AF:

0.00477

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68014

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

101

202

303

404

505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00509

Hom.:

Bravo

AF:

0.0165

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0502

AC:

221

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00437

AC:

530

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 17, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 23, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC26A4: PM5, BP4, BS1, BS2 -

not specified

Benign:5

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 14, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 18, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 16, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gly740Ser in exon 19 of SLC26A4: This variant is not expected to have clinical s ignificance due a common occurrence in the general population (dbSNP - rs1715435 3). -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Pendred syndrome

Benign:3

Apr 26, 2014

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Nov 06, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 4

Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Benign:1

May 06, 2022

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

0.072

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.068

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.43

.;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.0

N;N

PhyloP100

5.6

PrimateAI

Benign

0.48

PROVEAN

Benign

0.70

N;.

REVEL

Uncertain

0.40

Sift

Benign

0.091

T;.

Sift4G

Benign

0.16

T;.

Polyphen

0.0

B;B

Vest4

0.33

MVP

0.98

MPC

0.011

ClinPred

0.023

GERP RS

5.5

Varity_R

0.11

gMVP

0.60

Mutation Taster

=92/8

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