11-44114268-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_207122.2(EXT2):c.710C>T(p.Ser237Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,614,022 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 22 hom. )

Consequence

EXT2
NM_207122.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9O:1

Conservation

PhyloP100: 7.76

Publications

8 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013198048).

BP6

Variant 11-44114268-C-T is Benign according to our data. Variant chr11-44114268-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134212.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00223 (340/152290) while in subpopulation NFE AF = 0.00332 (226/68020). AF 95% confidence interval is 0.00297. There are 2 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2 link	c.710C>T	p.Ser237Leu	missense_variant	Exon 4 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.710C>T	p.Ser237Leu	missense_variant	Exon 4 of 14	1	NM_207122.2	ENSP00000431173.2		Q93063-1

Frequencies

GnomAD3 genomes

AF:

0.00223

AC:

340

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00527

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00332

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00269

AC:

677

AN:

251452

AF XY:

0.00249

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00577

Gnomad NFE exome

AF:

0.00422

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00392

AC:

5728

AN:

1461732

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

2701

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.000598

AC:

AN:

33472

American (AMR)

AF:

0.00134

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00535

AC:

286

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00465

AC:

5167

AN:

1111896

Other (OTH)

AF:

0.00296

AC:

179

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

310

620

929

1239

1549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<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:

0.00223

AC:

340

AN:

152290

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

166

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41558

American (AMR)

AF:

0.00229

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00527

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00332

AC:

226

AN:

68020

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

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:

0.00324

Hom.:

Bravo

AF:

0.00212

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00276

AC:

335

EpiCase

AF:

0.00322

EpiControl

AF:

0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

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

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EXT2: BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Exostoses, multiple, type 2

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2Other:1

Jul 10, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Nov 24, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

D;.;.;D

Eigen

Benign

0.067

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D;D;D

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Uncertain

0.73

MutationAssessor

Benign

1.0

L;L;.;L

PhyloP100

7.8

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.13

N;N;N;N

REVEL

Pathogenic

0.65

Sift

Benign

0.65

T;T;T;T

Sift4G

Benign

0.84

T;T;T;T

Polyphen

0.0090

B;B;.;B

Vest4

0.87

MVP

1.0

MPC

0.20

ClinPred

0.042

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.086

gMVP

0.83

Mutation Taster

=26/74

disease causing

(source)

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

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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