rs1554095397

Positions:

• chr5-149981580-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000112.4(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).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: SLC26A2 NM_000112.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 9.80

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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, 0.991
• 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: {Uncertain_significance=2, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A2	NM_000112.4	c.1987G>A	p.Gly663Arg	missense_variant	3/3	ENST00000286298.5	NP_000103.2
SLC26A2	XM_017009191.3	c.1987G>A	p.Gly663Arg	missense_variant	3/4		XP_016864680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A2	ENST00000286298.5	c.1987G>A	p.Gly663Arg	missense_variant	3/3	1	NM_000112.4	ENSP00000286298.4
SLC26A2	ENST00000503336.1	c.372+3229G>A		intron_variant		3		ENSP00000426053.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

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

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

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:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Achondrogenesis, type IB Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 12, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 24, 2023	- -

Diastrophic dysplasia;C0265274:Achondrogenesis, type IB;C1847593:Multiple epiphyseal dysplasia type 4;C1850554:Atelosteogenesis type II Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 27, 2022

This 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 submitter

clinical testing

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

Aug 19, 2024

Variant 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 submitter

clinical testing

Counsyl

Feb 03, 2017

- -

SLC26A2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 01, 2017

The 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
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

Other links and lift over

dbSNP: rs1554095397; hg19: chr5-149361143;