Variant 11-44124982-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2

The NM_207122.2(EXT2):c.937C>T(p.Gln313*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,460,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

EXT2
NM_207122.2 stop_gained, splice_region

Scores

Splicing: ADA: 0.9980

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.06

Variant links:

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]

EXT2 links:

EXT2 (HGNC:):

EXT2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-44124982-C-T is Pathogenic according to our data. Variant chr11-44124982-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44124982-C-T is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXT2	NM_207122.2 linkuse as main transcript	c.937C>T	p.Gln313*	stop_gained, splice_region_variant	5/14	ENST00000533608.7	NP_997005.1	Q93063-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXT2	ENST00000533608.7 linkuse as main transcript	c.937C>T	p.Gln313*	stop_gained, splice_region_variant	5/14	1	NM_207122.2	ENSP00000431173.2		Q93063-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250756

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135558

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:

0.00000882

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460134

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726444

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:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Exostoses, multiple, type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

This sequence change creates a premature translational stop signal (p.Gln313*) in the EXT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXT2 are known to be pathogenic (PMID: 10679937, 19810120). This variant is present in population databases (rs763718818, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with multiple osteochondromas (PMID: 16283885, 28849184). ClinVar contains an entry for this variant (Variation ID: 265134). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2021

Nonsense 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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17041877, 16283885, 33726816, 28849184) -

EXT2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 03, 2023

The EXT2 c.937C>T variant is predicted to result in premature protein termination (p.Gln313*). This variant has been reported in individuals with multiple osteochondromas (Wuyts et al. 2005. PubMed ID: 16283885; Table S1, Jennes et al. 2009. PubMed ID: 19810120; described as c.1036C>T/p.Gln346X in Xu et al. 2017. PubMed ID: 28849184). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-44146532-C-T). Nonsense variants in EXT2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

Vest4

0.92

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.76

SpliceAI score (max)

0.020

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