rs886041272

Positions:

• chr11-44108109-C-CTGCT

Variant summary

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

The NM_207122.2(EXT2):​c.398_401dup​(p.Met135AlafsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT2 NM_207122.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.91

Genes affected

EXT2 (HGNC:3513): (exostosin glycosyltransferase 2) This gene encodes one of two glycosyltransferases involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type II form of multiple exostoses. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [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 11-44108109-C-CTGCT is Pathogenic according to our data. Variant chr11-44108109-C-CTGCT is described in ClinVar as [Pathogenic]. Clinvar id is 279944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT2	NM_207122.2	c.398_401dup	p.Met135AlafsTer8	frameshift_variant	2/14	ENST00000533608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT2	ENST00000533608.7	c.398_401dup	p.Met135AlafsTer8	frameshift_variant	2/14	1	NM_207122.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Exostoses, multiple, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 07, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in EXT2 are known to be pathogenic (PMID: 10679937, 19810120). This variant has not been reported in the literature in individuals with EXT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 279944). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met135Alafs*8) in the EXT2 gene. It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2021

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886041272; hg19: chr11-44129659;