7-107661643-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000441.2(SLC26A4):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,366 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.90

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 links:

SLC26A4-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

SLC26A4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 9 pathogenic variants. Next in-frame start position is after 21 codons. Genomic position: 107661702. Lost 0.026 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-107661643-T-G is Pathogenic according to our data. Variant chr7-107661643-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2136582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.2T>G	p.Met1?	start_lost	Exon 2 of 21	ENST00000644269.2	NP_000432.1	O43511-1
SLC26A4-AS1	NR_028137.1 link	n.156A>C		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 link	c.2T>G	p.Met1?	start_lost	Exon 2 of 21		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000579

AC:

AN:

172798

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000738

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1410366

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32658

American (AMR)

AF:

0.00

AC:

AN:

38430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25416

East Asian (EAS)

AF:

0.0000265

AC:

AN:

37702

South Asian (SAS)

AF:

0.00

AC:

AN:

80854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091652

Other (OTH)

AF:

0.00

AC:

AN:

58824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000260

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:2

Mar 11, 2025

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 23, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC26A4 c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-06 in 172798 control chromosomes (gnomAD). c.2T>G has been observed in individuals affected with hearing loss or enlarged vestibular aqueduct (Lim_2011, Wu_2019). Another start-loss variant affecting this codon has been classified as pathogenic by our lab. The following publications have been ascertained in the context of this evaluation (PMID: 21986928, 31581539). ClinVar contains an entry for this variant (Variation ID: 2136582). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:2

Nov 11, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Experimental studies have shown that disruption of the initiator codon affects SLC26A4 function (PMID: 19204907). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 2136582). Disruption of the initiator codon has been observed in individuals with SLC26A4-related conditions (PMID: 17876604, 19204907, 21961810, 27997596). This variant is present in population databases (rs111033302, gnomAD 0.008%). This sequence change affects the initiator methionine of the SLC26A4 mRNA. The next in-frame methionine is located at codon 21. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.15

T;T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

0.20

PhyloP100

2.9

PROVEAN

Benign

-1.1

N;.;N

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

D;.;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

0.0

B;B;.

Vest4

0.90

MutPred

0.98

Gain of methylation at M1 (P = 0.0082);Gain of methylation at M1 (P = 0.0082);Gain of methylation at M1 (P = 0.0082);

MVP

0.92

ClinPred

0.93

GERP RS

3.8

Varity_R

0.89

gMVP

0.70

Mutation Taster

=12/188

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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7-107661643-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over