11-44107734-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_207122.2(EXT2):c.22A>G(p.Asn8Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXT2 NM_207122.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21394116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT2	NM_207122.2	c.22A>G	p.Asn8Asp	missense_variant	2/14	ENST00000533608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT2	ENST00000533608.7	c.22A>G	p.Asn8Asp	missense_variant	2/14	1	NM_207122.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Exostoses, multiple, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 16, 2023

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 8 of the EXT2 protein (p.Asn8Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with EXT2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T;.;.;.;T
Eigen	Benign	-0.087
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;N;.;N
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.63	N;D;N;N;N;N
REVEL	Benign	0.063
Sift	Benign	0.050	D;D;D;D;D;D
Sift4G	Benign	0.61	T;T;T;T;T;T
Polyphen		0.0060	B;.;.;B;.;B
Vest4		0.39
MutPred		0.30		Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);Loss of MoRF binding (P = 0.0205);.;Loss of MoRF binding (P = 0.0205);
MVP		0.58
MPC		0.28
ClinPred		0.83	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.43

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-44129284;