rs1554095397

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The ENST00000286298.5(SLC26A2):​c.1987G>A​(p.Gly663Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,094 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G663G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

SLC26A2
ENST00000286298.5 missense

Scores

14
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 9.80
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 Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a domain STAS (size 151) in uniprot entity S26A2_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in ENST00000286298.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 5-149981580-G-A is Pathogenic according to our data. Variant chr5-149981580-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 550616.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC26A2NM_000112.4 linkuse as main transcriptc.1987G>A p.Gly663Arg missense_variant 3/3 ENST00000286298.5 NP_000103.2
SLC26A2XM_017009191.3 linkuse as main transcriptc.1987G>A p.Gly663Arg missense_variant 3/4 XP_016864680.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC26A2ENST00000286298.5 linkuse as main transcriptc.1987G>A p.Gly663Arg missense_variant 3/31 NM_000112.4 ENSP00000286298 P1
SLC26A2ENST00000503336.1 linkuse as main transcriptc.372+3229G>A intron_variant 3 ENSP00000426053

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000198
AC:
29
AN:
1461840
Hom.:
0
Cov.:
34
AF XY:
0.0000179
AC XY:
13
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000705
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
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
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Achondrogenesis, type IB Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 24, 2023- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Aug 12, 2020- -
Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 27, 2022This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 663 of the SLC26A2 protein (p.Gly663Arg). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC26A2 function (PMID: 16642506). 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. ClinVar contains an entry for this variant (Variation ID: 550616). This missense change has been observed in individual(s) with SLC26A2-related conditions (PMID: 16642506, 31880411). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. -
Osteochondrodysplasia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 19, 2024Variant summary: SLC26A2 c.1987G>A (p.Gly663Arg) results in a non-conservative amino acid change located in the STAS domain (IPR002645) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251228 control chromosomes (gnomAD). However, the variant was reported in the Japanese population with an allele frequency of 0.0019 (jMorp database). This frequency is lower than the maximum expected allele frequency for a pathogenic variant in SLC26A2 causing Sulfate Transporter-Related Osteochondrodysplasias (0.003). The variant, c.1987G>A, has been reported in the literature in compound heterozygous- and homozygous state in multiple Japanese individuals (i.e. affected fetuses) with Sulfate Transporter-Related Osteochondrodysplasia (Maeda_2006, Sato_2019). These data indicate that the variant is very likely to be associated with disease. One of these publication reported that the variant protein was exclusively observed only in the cytoplasm in an eukaryotic expression system, whereas the wild-type protein was observed on the plasma membrane (with no cytoplasmic or nuclear staining), suggesting that it most likely represents a functionally null mutation, because it is improperly localized to the cytoplasm (Maeda_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16642506, 31880411). ClinVar contains an entry for this variant (Variation ID: 550616). Based on the evidence outlined above, the variant was classified as pathogenic. -
Multiple epiphyseal dysplasia type 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylFeb 03, 2017- -
SLC26A2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 01, 2017The SLC26A2 c.1987G>A (p.Gly663Arg) missense variant was reported in one fetus in a compound heterozygous state with a second missense variant. The patient was diagnosed with an intermediate phenotype between diastrophic dysplasia and atelosteogenesis, type II. The unaffected mother of the patient was a carrier of the p.Gly663Arg variant, which was absent in 48 healthy controls (Maeda et al. 2006). No patients were reported with achondrogenesis, multiple epiphyseal dysplasia or sulfate transporter-related osteochondrodysplasia. The p.Gly663Arg variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database, in a region with good sequence coverage and hence is presumed to be rare. Functionally, Maeda et al. (2006) showed that in HEK293 cells, the p.Gly663Arg variant protein was located within the cytoplasm as compared to wild type protein which was present along the plasma membrane of the cell, with no cytoplasmic or nuclear staining. Based on the evidence, the p.Gly663Arg variant is classified as a variant of unknown significance but suspicious for pathogenicity for SLC26A2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.90
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.96
D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.46
D
MutationAssessor
Pathogenic
3.5
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-7.4
D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.96
MutPred
0.96
Gain of ubiquitination at K668 (P = 0.1115);
MVP
0.99
MPC
0.35
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.98
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs1554095397; hg19: chr5-149361143; API