rs104893924

Positions:

chr5-149981550-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000112.4(SLC26A2):c.1957T>A(p.Cys653Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,006 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: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SLC26A2
NM_000112.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: 7.94

Variant links:

Genes affected

SLC26A2 (HGNC:10994): (solute carrier family 26 member 2) The diastrophic dysplasia sulfate transporter is a transmembrane glycoprotein implicated in the pathogenesis of several human chondrodysplasias. It apparently is critical in cartilage for sulfation of proteoglycans and matrix organization. [provided by RefSeq, Jul 2008]

SLC26A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain STAS (size 151) in uniprot entity S26A2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000112.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 5-149981550-T-A is Pathogenic according to our data. Variant chr5-149981550-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149981550-T-A is described in Lovd as [Likely_pathogenic]. Variant chr5-149981550-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A2	NM_000112.4 linkuse as main transcript	c.1957T>A	p.Cys653Ser	missense_variant	3/3	ENST00000286298.5	NP_000103.2
SLC26A2	XM_017009191.3 linkuse as main transcript	c.1957T>A	p.Cys653Ser	missense_variant	3/4		XP_016864680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A2	ENST00000286298.5 linkuse as main transcript	c.1957T>A	p.Cys653Ser	missense_variant	3/3	1	NM_000112.4	ENSP00000286298	P1
SLC26A2	ENST00000503336.1 linkuse as main transcript	c.372+3199T>A		intron_variant		3		ENSP00000426053

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251278

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000142

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000125

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2021	The SLC26A2 c.1957T>A; p.Cys653Ser variant (rs104893924) is one of the most frequently found pathogenic SLC26A2 variants and has been described in the homozygous and compound heterozygous states in individuals with recessive multiple epiphyseal dysplasia (rMED) and diastrophic dysplasia (DTD; Czarny-Ratajczak 2010, Hinrichs 2010, Makitie 2003, Rossi 2001). It contains an entry in ClinVar (Variation ID: 4098) and is observed in the European (non-Finnish) population at an overall frequency of 0.027% (35/129008 alleles) in the Genome Aggregation Database. The cysteine at codon 653 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. In addition, functional in vitro studies of the variant protein demonstrate reduced protein expression and sulfate transport function when compared to wild type protein (Karniski 2004). Based on available information, this variant is considered pathogenic. REFERENCES Czarny-Ratajczak M et al. New intermediate phenotype between MED and DD caused by compound heterozygous mutations in the DTDST gene. Am J Med Genet A. 2010; 152A(12): 3036-3042. Hinrichs T et al. Recessive multiple epiphyseal dysplasia (rMED) with homozygosity for C653S mutation in the DTDST gene--phenotype, molecular diagnosis and surgical treatment of habitual dislocation of multilayered patella: case report. BMC Musculoskelet Disord. 2010;11:110. Karniski L. Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells. Hum Mol Genet. 2004; 13(19): 2165-2171. Makitie O et al. Autosomal recessive multiple epiphyseal dysplasia with homozygosity for C653S in the DTDST gene: double-layer patella as a reliable sign. Am J Med Genet A. 2003;122A(3): 187-192. Rossi A et al. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat. 2001; 17(3): 159-171. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 22, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SLC26A2: PM3:Very Strong, PM2, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2023	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies revealed significantly reduced protein expression in cells with mutant protein, as compared to wild type cells (Karniski et al., 2004); This variant is associated with the following publications: (PMID: 12966518, 30578734, 35026467, 21077204, 20525296, 11241838, 21922596, 11448940, 29724173, 30423444, 29758562, 30462520, 28941661, 30080953, 31980526, 31589614, 33724725, 21155763, 34064542, 33728303, 32633442, 34958143, 34974531, 15294877, 12525546) -

Achondrogenesis, type IB

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 653 of the SLC26A2 protein (p.Cys653Ser). This variant is present in population databases (rs104893924, gnomAD 0.03%). This missense change has been observed in individuals with diastrophic dysplasia or epiphyseal dysplasia (PMID: 11241838, 12966518, 20525296, 21077204). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4098). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC26A2 function (PMID: 15294877). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Aug 13, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 10, 2022	- -

Diastrophic dysplasia

Pathogenic:2Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 09, 2020	- -

Multiple epiphyseal dysplasia type 4

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 15, 2003	- -

SLC26A2-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1957T>A;p.(Cys653Ser) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 4098; PMID: 20301524; 11241838; 12966518; 20525296; 21077204; 21922596) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 11448940; 15294877) - PS3_moderate. The variant is present at low allele frequencies population databases (rs104893924– gnomAD 0.001249%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Cys653Ser) was detected in trans with a pathogenic variant (PMID: 12966518; 20525296; 21077204; 21922596) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 21077204) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 23, 2024	The SLC26A2 c.1957T>A variant is predicted to result in the amino acid substitution p.Cys653Ser. This variant has been documented to be causative for SLC26A2-related disorders (Makitie et al. 2003. PubMed ID: 12966518; Hinrichs et al. 2010. PubMed ID: 20525296; Czarny-Ratajczak et al. 2010. PubMed ID: 21077204). This variant is reported in 0.027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Atelosteogenesis type II

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Mar 11, 2016

- -

Sulfate transporter-related osteochondrodysplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 07, 2018

Variant summary: SLC26A2 c.1957T>A (p.Cys653Ser) results in a non-conservative amino acid change located in the STAS domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 276994 control chromosomes (gnomAD). The variant, c.1957T>A, has been reported in the literature in multiple homozygote and compound heterozygote individuals affected with recessive Multiple epiphyseal dysplasia (Ballhausen_2003, Jackson_2012). These data indicate that the variant is very likely to be associated with disease. A functional study, Karniski_2004, found the variant to have ~55% stimulated sulfate transport. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

3MC syndrome 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Dec 24, 2019

NM_000112.3(SLC26A2):c.1957T>A(C653S) is classified as likely pathogenic in the context of SLC26A2-related disorders and is associated with autosomal recessive multiple epiphyseal dysplasia. Sources cited for classification include the following: PMID 21922596, 20525296, 12966518, 21077204, 15294877, 11448940, 11241838, and 12525546. Classification of NM_000112.3(SLC26A2):c.1957T>A(C653S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Connective tissue disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.92

MutPred

0.91

Loss of catalytic residue at I651 (P = 0.1057);

MVP

1.0

MPC

0.35

ClinPred

0.90

GERP RS

6.0

Varity_R

0.94

gMVP

0.85

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