chr11-44130075-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_207122.2(EXT2):c.1110G>T(p.Met370Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000957 in 1,614,152 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M370T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0050 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00054 ( 7 hom. )

Consequence

EXT2
NM_207122.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 2.33

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

exostoses, multiple, type 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P
seizures-scoliosis-macrocephaly syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
hereditary multiple osteochondromas
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EXT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006648153).

BP6

Variant 11-44130075-G-T is Benign according to our data. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-44130075-G-T is described in CliVar as Benign. Clinvar id is 134217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00497 (757/152298) while in subpopulation AFR AF = 0.0171 (710/41562). AF 95% confidence interval is 0.016. There are 6 homozygotes in GnomAd4. There are 371 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2 link	c.1110G>T	p.Met370Ile	missense_variant	Exon 7 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.1110G>T	p.Met370Ile	missense_variant	Exon 7 of 14	1	NM_207122.2	ENSP00000431173.2		Q93063-1

Frequencies

GnomAD3 genomes

AF:

0.00498

AC:

758

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0172

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00132

AC:

332

AN:

251456

AF XY:

0.000876

show subpopulations

Gnomad AFR exome

AF:

0.0180

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000538

AC:

787

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000465

AC XY:

338

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0196

AC:

656

AN:

33474

American (AMR)

AF:

0.00132

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111986

Other (OTH)

AF:

0.00111

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00497

AC:

757

AN:

152298

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

371

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0171

AC:

710

AN:

41562

American (AMR)

AF:

0.00222

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00198

Hom.:

Bravo

AF:

0.00560

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0148

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00165

AC:

200

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Exostoses, multiple, type 2

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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

Benign:2

Jan 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29529714) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.55

D;.;.;D

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

.;T;T;T

MetaRNN

Benign

0.0066

T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

0.51

N;N;.;N

PhyloP100

2.3

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.16

N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.33

T;T;T;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.0

B;B;.;B

Vest4

0.20

MutPred

0.44

Loss of ubiquitination at K369 (P = 0.0454);Loss of ubiquitination at K369 (P = 0.0454);.;Loss of ubiquitination at K369 (P = 0.0454);

MVP

0.95

MPC

0.24

ClinPred

0.011

GERP RS

2.7

Varity_R

0.054

gMVP

0.54

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over