rs864309638

Variant names:

• chr11-44124787-A-C
• rs864309638
• NM_207122.2:c.744-2A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-44124787-A-C
• chr11-44124787-A-G

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.744-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT2 NM_207122.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.72

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 8.8, offset of 31, new splice context is: acttcctcctgtcatctcAGgtg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-44124787-A-C is Pathogenic according to our data. Variant chr11-44124787-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44124787-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2	c.744-2A>C		splice_acceptor_variant, intron_variant	Intron 4 of 13	ENST00000533608.7	NP_997005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT2	ENST00000533608.7	c.744-2A>C		splice_acceptor_variant, intron_variant	Intron 4 of 13	1	NM_207122.2	ENSP00000431173.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Exostoses, multiple, type 2 Pathogenic:3

Mar 01, 2019

Breda Genetics srl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant c.843-2A>C in the EXT2 gene is reported as pathogenic for multiple exostoses type 2 in ClinVar (Variation ID: 2477). This variant has been originally identified by Heinritz et al. (2009) in a male patient who was reported to have also an affected son. This nucleotide substitution results in two different skipping events: either only exon 5 or exons 5 and 6. Loss of exon 5 results in a frameshift with premature termination 18 amino acids downstream (p.Pro249Argfs*18), while loss of exons 5 and 6 leads to the in-frame deletion p.Pro249_Arg360del (PMID: 19344451). This variant has not been reported in gnomAD, 1000 Genomes, NHLI Exome Sequencing Project (ESP), or LOVD database v.3.0. -

Apr 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change affects an acceptor splice site in intron 4 of the EXT2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EXT2 are known to be pathogenic (PMID: 10679937, 19810120). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hereditary multiple osteochondromatosis (PMID: 19344451; Invitae). ClinVar contains an entry for this variant (Variation ID: 2477). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 19344451). -

May 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

EXT2-related disorder Pathogenic:1

Aug 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EXT2 c.744-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in an individual with multiple osteochondromas (Heinritz et al. 2009. PubMed ID: 19344451). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site 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	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	34
DANN	Benign	0.95
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.78		Position offset: 33
DS_AL_spliceai		0.98		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs864309638; hg19: chr11-44146337;