rs112082531

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.-31+474G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,535,772 control chromosomes in the GnomAD database, including 713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 50 hom., cov: 32)

Exomes 𝑓: 0.028 ( 663 hom. )

Consequence

EXT2
NM_207122.2 intron

Scores

Splicing: ADA: 0.9939

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.802

Publications

3 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=-0.58).

BP6

Variant 11-44096326-G-A is Benign according to our data. Variant chr11-44096326-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1182129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0217 (3300/152270) while in subpopulation NFE AF = 0.0322 (2189/68010). AF 95% confidence interval is 0.0311. There are 50 homozygotes in GnomAd4. There are 1574 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 50 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXT2	NM_207122.2 link	c.-31+474G>A		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.-31+474G>A		intron_variant	Intron 1 of 13	1	NM_207122.2	ENSP00000431173.2		Q93063-1

Frequencies

GnomAD3 genomes

AF:

0.0217

AC:

3297

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00671

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0167

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0339

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0322

Gnomad OTH

AF:

0.0249

GnomAD2 exomes

AF:

0.0205

AC:

2801

AN:

136450

AF XY:

0.0207

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.0209

Gnomad EAS exome

AF:

0.0000951

Gnomad FIN exome

AF:

0.0355

Gnomad NFE exome

AF:

0.0326

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0283

AC:

39167

AN:

1383502

Hom.:

663

Cov.:

AF XY:

0.0279

AC XY:

19020

AN XY:

682722

show subpopulations

African (AFR)

AF:

0.00674

AC:

213

AN:

31584

American (AMR)

AF:

0.0138

AC:

492

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.0207

AC:

521

AN:

25168

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35724

South Asian (SAS)

AF:

0.00779

AC:

617

AN:

79216

European-Finnish (FIN)

AF:

0.0329

AC:

1114

AN:

33910

Middle Eastern (MID)

AF:

0.0298

AC:

168

AN:

5632

European-Non Finnish (NFE)

AF:

0.0319

AC:

34401

AN:

1078684

Other (OTH)

AF:

0.0283

AC:

1640

AN:

57886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1822

3643

5465

7286

9108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0217

AC:

3300

AN:

152270

Hom.:

Cov.:

AF XY:

0.0211

AC XY:

1574

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00674

AC:

280

AN:

41554

American (AMR)

AF:

0.0167

AC:

255

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00539

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0339

AC:

360

AN:

10620

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0322

AC:

2189

AN:

68010

Other (OTH)

AF:

0.0246

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

158

316

474

632

790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0268

Hom.:

Bravo

AF:

0.0202

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 06, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

0.80

PromoterAI

-0.13

Neutral

(source)

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.70

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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rs112082531

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