Variant 7-107712545-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000441.2(SLC26A4):c.2242C>G(p.Leu748Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,546,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.51

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 272) in uniprot entity S26A4_HUMAN there are 26 pathogenic changes around while only 8 benign (76%) in NM_000441.2

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15345058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.2242C>G	p.Leu748Val	missense_variant	20/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.2242C>G	p.Leu748Val	missense_variant	20/21		NM_000441.2	ENSP00000494017	P1	O43511-1
SLC26A4	ENST00000492030.2 linkuse as main transcript	n.428C>G		non_coding_transcript_exon_variant	5/6	5
SLC26A4	ENST00000644846.1 linkuse as main transcript	c.*144C>G		3_prime_UTR_variant, NMD_transcript_variant	9/10			ENSP00000494344

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251220

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000789

AC:

AN:

1394410

Hom.:

Cov.:

AF XY:

0.0000100

AC XY:

AN XY:

697734

show subpopulations

Gnomad4 AFR exome

AF:

0.000249

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000779

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.52e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 13, 2013

The Leu748Val variant in SLC26A4 has not been previously reported in individuals with hearing loss or in large population studies. Computational tools (amino a cid biochemical properties, conservation, SIFT, AlignGVGD, PolyPhen-2) suggest t hat this variant may not impact the protein, though this information is not pred ictive enough to rule out pathogenicity. In summary, additional information is n eeded to determine the clinical significance of this variant. -

Pendred syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.70

.;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.90

L;L

MutationTaster

Benign

0.92

N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.50

N;.

REVEL

Uncertain

0.38

Sift

Benign

0.10

T;.

Sift4G

Benign

0.23

T;.

Polyphen

0.11

B;B

Vest4

0.48

MVP

0.84

MPC

0.014

ClinPred

0.14

GERP RS

4.7

Varity_R

0.073

gMVP

0.53

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