rs786200881

chr5-149978040-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000112.4(SLC26A2):c.391del(p.Leu131CysfsTer41) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S130S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A2 NM_000112.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.08

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-149978040-TC-T is Pathogenic according to our data. Variant chr5-149978040-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-149978040-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A2	NM_000112.4	c.391del	p.Leu131CysfsTer41	frameshift_variant	2/3	ENST00000286298.5
SLC26A2	XM_017009191.3	c.391del	p.Leu131CysfsTer41	frameshift_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A2	ENST00000286298.5	c.391del	p.Leu131CysfsTer41	frameshift_variant	2/3	1	NM_000112.4	P1
SLC26A2	ENST00000503336.1	c.64del	p.Leu22CysfsTer41	frameshift_variant	1/2	3
SLC26A2	ENST00000690410.1	n.623del		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atelosteogenesis type II Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1996	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 24, 2016	- -

Multiple epiphyseal dysplasia type 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 24, 2016

- -

Achondrogenesis, type IB Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 24, 2016

- -

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

Sep 21, 2023

This premature translational stop signal has been observed in individual(s) with atelosteogenesis type 2 (PMID: 8931695). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4088). This variant is also known as delta-c418. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu131Cysfs*41) in the SLC26A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC26A2 are known to be pathogenic (PMID: 7923357, 10482955, 11241838). -

Diastrophic dysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 24, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs786200881; hg19: chr5-149357603;