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

11
7
1

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]

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 rank MANE Protein UniProt
SLC26A2NM_000112.4 linkc.1957T>A p.Cys653Ser missense_variant Exon 3 of 3 ENST00000286298.5 NP_000103.2 P50443
SLC26A2XM_017009191.3 linkc.1957T>A p.Cys653Ser missense_variant Exon 3 of 4 XP_016864680.1 P50443

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC26A2ENST00000286298.5 linkc.1957T>A p.Cys653Ser missense_variant Exon 3 of 3 1 NM_000112.4 ENSP00000286298.4 P50443
SLC26A2ENST00000503336.1 linkc.372+3199T>A intron_variant Intron 1 of 1 3 ENSP00000426053.1 H0YA38

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152156
Hom.:
0
Cov.:
32
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:
28
AN:
251278
Hom.:
0
AF XY:
0.000133
AC XY:
18
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.:
0
Cov.:
34
AF XY:
0.000132
AC XY:
96
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:
19
AN:
152156
Hom.:
0
Cov.:
32
AF XY:
0.000135
AC XY:
10
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.:
0
Bravo
AF:
0.0000831
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000988
AC:
12
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
Jul 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SLC26A2: PM3:Very Strong, PM2, PP4, PS3:Supporting -

Feb 05, 2021
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jan 13, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Oct 14, 2014
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 22, 2019
Revvity Omics, Revvity
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 30, 2019
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 02, 2014
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Achondrogenesis, type IB Pathogenic:3
Mar 30, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 24, 2019
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:3
Jan 07, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Aug 13, 2016
Division of Human Genetics, Children's Hospital of Philadelphia
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

May 08, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Diastrophic dysplasia Pathogenic:2Other:1
Dec 24, 2019
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Nov 09, 2020
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

SLC26A2-related disorder Pathogenic:2
Jan 05, 2022
DASA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 23, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. -

Multiple epiphyseal dysplasia type 4 Pathogenic:2
Dec 24, 2019
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Oct 15, 2003
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Atelosteogenesis type II Pathogenic:1
Mar 11, 2016
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sulfate transporter-related osteochondrodysplasia Pathogenic:1
Jun 07, 2018
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Dec 24, 2019
Myriad Genetics, Inc.
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Mar 01, 2020
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.78
D
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.89
D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Pathogenic
3.3
M
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-7.4
D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.92
MutPred
0.91
Loss of catalytic residue at I651 (P = 0.1057);
MVP
1.0
MPC
0.35
ClinPred
0.90
D
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.

Other links and lift over

dbSNP: rs104893924; hg19: chr5-149361113; API