11-44107972-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_207122.2(EXT2):c.260T>G(p.Met87Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000324 in 1,614,200 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 1 hom. )

Consequence

EXT2
NM_207122.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4O:1

Conservation

PhyloP100: 6.15

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 11-44107972-T-G is Benign according to our data. Variant chr11-44107972-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134211.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=2, not_provided=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000302 (46/152332) while in subpopulation NFE AF= 0.000588 (40/68024). AF 95% confidence interval is 0.000444. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2 link	c.260T>G	p.Met87Arg	missense_variant	Exon 2 of 14	ENST00000533608.7	NP_997005.1	Q93063-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXT2	ENST00000533608.7 link	c.260T>G	p.Met87Arg	missense_variant	Exon 2 of 14	1	NM_207122.2	ENSP00000431173.2		Q93063-1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000354

AC:

AN:

251194

Hom.:

AF XY:

0.000390

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000521

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:

0.000608

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000326

AC:

477

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

220

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000381

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000302

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000522

Hom.:

Bravo

AF:

0.000268

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Exostoses, multiple, type 2

Benign:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2021

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Uncertain:1Benign:1

Mar 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26246518) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Nov 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: EXT2 c.260T>G (p.Met87Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251194 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EXT2 causing Seizures, Scoliosis, And Macrocephaly Syndrome, allowing no conclusion about variant significance. c.260T>G has been reported in the literature in the homozygous state in cis with another variant of uncertain significance in four related individuals affected with Seizures, Scoliosis, And Macrocephaly Syndrome without osteochondromas reported in the family and has also been reported without strong evidence for causality in at least one individual with multiple osteochondromas (e.g. Farhan_2015, Gnoli_2024). These reports do not provide unequivocal conclusions about association of the variant with Seizures, Scoliosis, And Macrocephaly Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in >75%-90% of WT protein expression in vitro (Farhan_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26246518, 38351015). ClinVar contains an entry for this variant (Variation ID: 134211). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;.;.;.;D

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.61

D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.1

M;.;M;.;M

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.5

N;D;N;D;N

REVEL

Pathogenic

0.86

Sift

Benign

0.055

T;D;T;D;T

Sift4G

Benign

0.22

T;D;T;T;T

Polyphen

0.94

P;.;D;.;P

Vest4

0.97

MVP

1.0

MPC

0.83

ClinPred

0.20

GERP RS

5.5

Varity_R

0.65

gMVP

0.97

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

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