Genetic Variant EXT2:p.Ala173Ala (chr11-44108231-G-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_207122.2(EXT2):c.519G>C(p.Ala173Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00836 in 1,612,728 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A173A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0062 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0086 ( 63 hom. )

Consequence

EXT2
NM_207122.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.06

Publications

3 publications found

Variant links:

COSMIC-nc: COSV59151235

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 11-44108231-G-C is Benign according to our data. Variant chr11-44108231-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 304577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.07 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00624 (950/152276) while in subpopulation NFE AF = 0.00973 (662/68010). AF 95% confidence interval is 0.00912. There are 6 homozygotes in GnomAd4. There are 457 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207122.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EXT2	NM_207122.2	MANE Select	c.519G>C	p.Ala173Ala	synonymous	Exon 2 of 14	NP_997005.1
EXT2	NM_000401.3		c.618G>C	p.Ala206Ala	synonymous	Exon 2 of 14	NP_000392.3
EXT2	NM_001178083.3		c.519G>C	p.Ala173Ala	synonymous	Exon 2 of 15	NP_001171554.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EXT2	ENST00000533608.7	TSL:1 MANE Select	c.519G>C	p.Ala173Ala	synonymous	Exon 2 of 14	ENSP00000431173.2
EXT2	ENST00000358681.8	TSL:1	c.519G>C	p.Ala173Ala	synonymous	Exon 2 of 15	ENSP00000351509.4
EXT2	ENST00000343631.4	TSL:1	c.519G>C	p.Ala173Ala	synonymous	Exon 3 of 15	ENSP00000342656.3

Frequencies

GnomAD3 genomes

AF:

0.00624

AC:

949

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0127

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00973

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00624

AC:

1555

AN:

249074

AF XY:

0.00633

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00200

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0146

Gnomad NFE exome

AF:

0.00918

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00859

AC:

12540

AN:

1460452

Hom.:

Cov.:

AF XY:

0.00844

AC XY:

6133

AN XY:

726570

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33476

American (AMR)

AF:

0.00179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00451

AC:

118

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.00205

AC:

177

AN:

86252

European-Finnish (FIN)

AF:

0.0123

AC:

639

AN:

52036

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0100

AC:

11122

AN:

1111982

Other (OTH)

AF:

0.00601

AC:

363

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

695

1389

2084

2778

3473

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.00624

AC:

950

AN:

152276

Hom.:

Cov.:

AF XY:

0.00614

AC XY:

457

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

41570

American (AMR)

AF:

0.00248

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0127

AC:

135

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00973

AC:

662

AN:

68010

Other (OTH)

AF:

0.00332

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00520

Hom.:

Bravo

AF:

0.00502

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00769

EpiControl

AF:

0.00599

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Exostoses, multiple, type 2

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EXT2: BP4, BP7, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Exostoses, multiple, type 2;C4225248:Seizures-scoliosis-macrocephaly syndrome

Benign:1

Sep 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Exostoses, multiple, type 1

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.066

(source)

DANN

Benign

0.36

PhyloP100

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=89/11

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over