rs386833497

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000112.4(SLC26A2):c.1650del(p.Ser551ValfsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

SLC26A2
NM_000112.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 0.997

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 11 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-149981242-AG-A is Pathogenic according to our data. Variant chr5-149981242-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 56016.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=2, Uncertain_significance=1}. Variant chr5-149981242-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A2	NM_000112.4 linkuse as main transcript	c.1650del	p.Ser551ValfsTer34	frameshift_variant	3/3	ENST00000286298.5
SLC26A2	XM_017009191.3 linkuse as main transcript	c.1650del	p.Ser551ValfsTer34	frameshift_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A2	ENST00000286298.5 linkuse as main transcript	c.1650del	p.Ser551ValfsTer34	frameshift_variant	3/3	1	NM_000112.4	P1
SLC26A2	ENST00000503336.1 linkuse as main transcript	c.372+2892del		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152206

Hom.:

Cov.:

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:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250808

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000881

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000739

AC:

108

AN:

1461836

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727216

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:

0.0000953

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Achondrogenesis, type IB

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 09, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 28, 2020	- -

Multiple epiphyseal dysplasia type 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

literature only

Counsyl

Jan 23, 2015

- -

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

Invitae

Jan 12, 2024

This sequence change creates a premature translational stop signal (p.Ser551Valfs*34) in the SLC26A2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 189 amino acid(s) of the SLC26A2 protein. This variant is present in population databases (rs386833497, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of SLC26A2-related conditions (PMID: 11241838). ClinVar contains an entry for this variant (Variation ID: 56016). This variant disrupts a region of the SLC26A2 protein in which other variant(s) (p.Glu703Glyfs*9) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sulfate transporter-related osteochondrodysplasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 29, 2022

Variant summary: SLC26A2 c.1650delG (p.Ser551ValfsX34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Disatrophic Dysplasia in HGMD. The variant allele was found at a frequency of 8e-06 in 250808 control chromosomes. c.1650delG has been reported in the literature in individual(s) affected with Diastrophic Dysplasia (Rossi_2001). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as: Pathogenic (n=1), Likely Pathogenic (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 18, 2021

Frameshift variant predicted to result in protein truncation, as the last 189 amino acids are replaced with 33 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Identified in a patient with diastrophic dysplasia in the published literature (Rossi et al., 2001); This variant is associated with the following publications: (PMID: 11241838) -

Diastrophic dysplasia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

- -

SLC26A2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 01, 2016

The SLC26A2 c.1650delG (p.Ser551ValfsTer34) variant, which is also reported as c.1677delG, results in a frameshift and is predicted to result in premature termination of the protein. The p.Ser551ValfsTer34 variant was reported in a single study in which it was found in one individual with diastrophic dysplasia, although zygosity information was not provided (Rossi et al. 2001). The p.Ser551ValfsTer34 variant was absent from 100 controls and is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on a single allele in a region of good sequence coverage, so the variant is presumed to be rare. Due to the potential impact of frameshift variants and the lack of clarifying evidence, the p.Ser551ValfsTer34 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

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