Variant chr5-149981315-TA-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000112.4(SLC26A2):c.1724delA(p.Lys575fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

SLC26A2
NM_000112.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.760

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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 4 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-149981315-TA-T is Pathogenic according to our data. Variant chr5-149981315-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 4087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149981315-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A2	NM_000112.4 link	c.1724delA	p.Lys575fs	frameshift_variant	3/3	ENST00000286298.5	NP_000103.2	P50443
SLC26A2	XM_017009191.3 link	c.1724delA	p.Lys575fs	frameshift_variant	3/4		XP_016864680.1	P50443

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A2	ENST00000286298.5 link	c.1724delA	p.Lys575fs	frameshift_variant	3/3	1	NM_000112.4	ENSP00000286298.4		P50443
SLC26A2	ENST00000503336.1 link	c.372+2966delA		intron_variant		3		ENSP00000426053.1		H0YA38

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152218

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251246

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135810

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Achondrogenesis, type IB

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1996	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Nov 24, 2021	The homozygous frameshift deletion variant c.1724delA has been previously reported as c.1751delA by Superti-Furga A et al in 1996 in a Dutch patient. The allele frequency-0.0048% in gnomAD (aggregated) database and 0.0058% in 1000g. Phenotype observed in the proband was cystic hygroma, generalized subcutaneous edema with skin thickening, hypoechogenic area and distorted fetal limbs. Achondrogensis IB is an autosomal recessive disorder. Based on the phenotypic observation and the available literature, we classify this variant as pathogenic. -

Diastrophic dysplasia

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 1996	- -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 10, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change creates a premature translational stop signal (p.Lys575Serfs*10) in the SLC26A2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 165 amino acid(s) of the SLC26A2 protein. This variant is present in population databases (rs749382145, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with achondrogenesis, atelosteogenesis, and diastrophic dysplasia (PMID: 7923357, 8528239, 8571951; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4087). For these reasons, this variant has been classified as Pathogenic. -

Atelosteogenesis type II

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1996

- -

Sulfate transporter-related osteochondrodysplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 26, 2017

Variant summary: The SLC26A2 c.1724delA (p.Lys575Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent SLC26A2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121446 control chromosomes. This variant has been reported in multiple affected individuals and classified as pathogenic/likely pathogenic by clinical diagnostic laboratories and reputable databases. Taken together, this variant is classified as pathogenic. -

Connective tissue disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2019

- -

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