Genetic Variant EXT2:c.-30-147A>T (chr11-44107536-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_207122.2(EXT2):c.-30-147A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 730,360 control chromosomes in the GnomAD database, including 28,260 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5056 hom., cov: 32)

Exomes 𝑓: 0.28 ( 23204 hom. )

Consequence

EXT2
NM_207122.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.571

Publications

2 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 (BayesDel_noAF=-0.97).

BP6

Variant 11-44107536-A-T is Benign according to our data. Variant chr11-44107536-A-T is described in ClinVar as [Benign]. Clinvar id is 1289926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2 link	c.-30-147A>T		intron_variant	Intron 1 of 13	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.-30-147A>T		intron_variant	Intron 1 of 13	1	NM_207122.2	ENSP00000431173.2		Q93063-1

Frequencies

GnomAD3 genomes

AF:

0.245

AC:

37192

AN:

151888

Hom.:

5049

Cov.:

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.224

Gnomad AMR

AF:

0.222

Gnomad ASJ

AF:

0.331

Gnomad EAS

AF:

0.338

Gnomad SAS

AF:

0.161

Gnomad FIN

AF:

0.361

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.289

Gnomad OTH

AF:

0.251

GnomAD4 exome

AF:

0.276

AC:

159792

AN:

578354

Hom.:

23204

AF XY:

0.271

AC XY:

81037

AN XY:

298758

show subpopulations

African (AFR)

AF:

0.144

AC:

2111

AN:

14688

American (AMR)

AF:

0.202

AC:

3817

AN:

18858

Ashkenazi Jewish (ASJ)

AF:

0.330

AC:

4772

AN:

14478

East Asian (EAS)

AF:

0.321

AC:

10154

AN:

31616

South Asian (SAS)

AF:

0.157

AC:

7275

AN:

46400

European-Finnish (FIN)

AF:

0.357

AC:

10678

AN:

29944

Middle Eastern (MID)

AF:

0.291

AC:

660

AN:

2270

European-Non Finnish (NFE)

AF:

0.288

AC:

112210

AN:

390040

Other (OTH)

AF:

0.270

AC:

8115

AN:

30060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

5783

11566

17348

23131

28914

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.245

AC:

37232

AN:

152006

Hom.:

5056

Cov.:

AF XY:

0.247

AC XY:

18316

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.143

AC:

5925

AN:

41482

American (AMR)

AF:

0.221

AC:

3379

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

1148

AN:

3468

East Asian (EAS)

AF:

0.338

AC:

1746

AN:

5160

South Asian (SAS)

AF:

0.162

AC:

781

AN:

4816

European-Finnish (FIN)

AF:

0.361

AC:

3800

AN:

10538

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.289

AC:

19634

AN:

67954

Other (OTH)

AF:

0.248

AC:

525

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1387

2775

4162

5550

6937

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.272

Hom.:

768

Bravo

AF:

0.233

Asia WGS

AF:

0.206

AC:

717

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

1.0

(source)

DANN

Benign

0.46

PhyloP100

-0.57

Mutation Taster

=100/0

polymorphism (auto)

(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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11-44107536-A-T

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