rs148711133

chr11-44206885-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_207122.2(EXT2):c.1588G>A(p.Glu530Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,108 control chromosomes in the GnomAD database, including 2 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 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

EXT2
NM_207122.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 8.00

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06113264).

BP6

Variant 11-44206885-G-A is Benign according to our data. Variant chr11-44206885-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263287.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr11-44206885-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXT2	NM_207122.2 linkuse as main transcript	c.1588G>A	p.Glu530Lys	missense_variant	10/14	ENST00000533608.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXT2	ENST00000533608.7 linkuse as main transcript	c.1588G>A	p.Glu530Lys	missense_variant	10/14	1	NM_207122.2	P1	Q93063-1

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000581

AC:

146

AN:

251436

Hom.:

AF XY:

0.000589

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00107

AC:

1565

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

727

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.00133

Gnomad4 OTH exome

AF:

0.000811

GnomAD4 genome

AF:

0.000742

AC:

113

AN:

152278

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.000744

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000585

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The EXT2 p.E563K variant was identified in 1 individual with MâˆšÂºllerian adenosarcoma (Howitt_2015_PMID:25231023). The variant was identified in dbSNP (ID: rs148711133) and ClinVar (classified as likely benign by Prevention Genetics and Invitae; and as uncertain significance by EGL Genetic Diagnostics). This variant was not found in COSMIC. The variant was identified in control databases in 166 of 282838 chromosomes (1 homozygous) at a frequency of 0.0005869, and was observed at the highest frequency in the European (non-Finnish) population in 148 of 129156 chromosomes (freq: 0.001146) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.E563 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

The c.1588G>A (p.E530K) alteration is located in exon 10 (coding exon 9) of the EXT2 gene. This alteration results from a G to A substitution at nucleotide position 1588, causing the glutamic acid (E) at amino acid position 530 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Exostoses, multiple, type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Pathogenic

0.18

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.;.;D

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.017

MetaRNN

Benign

0.061

T;T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.4

L;.;.;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-2.5

N;N;N;N

REVEL

Uncertain

0.51

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.99

D;D;.;D

Vest4

0.87

MVP

0.87

MPC

0.69

ClinPred

0.062

GERP RS

5.0

Varity_R

0.44

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over