rs386833502

Variant names:

• chr5-149977905-GC-G
• rs386833502
• NM_000112.4:c.255delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000112.4(SLC26A2):​c.255delC​(p.Asn87IlefsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A85A) 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: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.231
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• achondrogenesis type IB

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, ClinGen
• atelosteogenesis type II

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics
• diastrophic dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• multiple epiphyseal dysplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• multiple epiphyseal dysplasia type 4

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 5-149977905-GC-G is Pathogenic according to our data. Variant chr5-149977905-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56021.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A2	NM_000112.4	c.255delC	p.Asn87IlefsTer2	frameshift_variant	Exon 2 of 3	ENST00000286298.5	NP_000103.2
SLC26A2	XM_017009191.3	c.255delC	p.Asn87IlefsTer2	frameshift_variant	Exon 2 of 4		XP_016864680.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A2	ENST00000286298.5	c.255delC	p.Asn87IlefsTer2	frameshift_variant	Exon 2 of 3	1	NM_000112.4	ENSP00000286298.4
SLC26A2	ENST00000690410.1	n.487delC		non_coding_transcript_exon_variant	Exon 2 of 2
SLC26A2	ENST00000503336.1	c.-74delC		upstream_gene_variant		3		ENSP00000426053.1
SLC26A2	ENST00000433184.1	c.*184delC		downstream_gene_variant		4		ENSP00000405496.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Diastrophic dysplasia Pathogenic:1

-

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386833502; hg19: chr5-149357468;