rs2302427

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_004456.5(EZH2):c.553G>C(p.Asp185His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0737 in 1,612,676 control chromosomes in the GnomAD database, including 4,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.062 ( 394 hom., cov: 32)

Exomes 𝑓: 0.075 ( 4546 hom. )

Consequence

EZH2
NM_004456.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 7.28

Variant links:

Genes affected

EZH2 (HGNC:3527): (enhancer of zeste 2 polycomb repressive complex 2 subunit) This gene encodes a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. This protein associates with the embryonic ectoderm development protein, the VAV1 oncoprotein, and the X-linked nuclear protein. This protein may play a role in the hematopoietic and central nervous systems. Multiple alternatively splcied transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Feb 2011]

EZH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the EZH2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 38 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 4.6808 (above the threshold of 3.09). Trascript score misZ: 5.1095 (above the threshold of 3.09). GenCC associations: The gene is linked to Weaver syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.00156039).

BP6

Variant 7-148828812-C-G is Benign according to our data. Variant chr7-148828812-C-G is described in ClinVar as [Benign]. Clinvar id is 134224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148828812-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5 link	c.553G>C	p.Asp185His	missense_variant	Exon 6 of 20	ENST00000320356.7	NP_004447.2	Q15910-2A0A090N8E9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7 link	c.553G>C	p.Asp185His	missense_variant	Exon 6 of 20	1	NM_004456.5	ENSP00000320147.2		Q15910-2

Frequencies

GnomAD3 genomes

AF:

0.0622

AC:

9447

AN:

151914

Hom.:

396

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0139

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0510

Gnomad ASJ

AF:

0.0948

Gnomad EAS

AF:

0.173

Gnomad SAS

AF:

0.0827

Gnomad FIN

AF:

0.0942

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0773

Gnomad OTH

AF:

0.0733

GnomAD3 exomes

AF:

0.0783

AC:

19436

AN:

248352

Hom.:

990

AF XY:

0.0802

AC XY:

10781

AN XY:

134452

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.0359

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.176

Gnomad SAS exome

AF:

0.0716

Gnomad FIN exome

AF:

0.0973

Gnomad NFE exome

AF:

0.0810

Gnomad OTH exome

AF:

0.0805

GnomAD4 exome

AF:

0.0749

AC:

109369

AN:

1460644

Hom.:

4546

Cov.:

AF XY:

0.0752

AC XY:

54645

AN XY:

726566

show subpopulations

Gnomad4 AFR exome

AF:

0.0120

Gnomad4 AMR exome

AF:

0.0368

Gnomad4 ASJ exome

AF:

0.0999

Gnomad4 EAS exome

AF:

0.121

Gnomad4 SAS exome

AF:

0.0716

Gnomad4 FIN exome

AF:

0.0959

Gnomad4 NFE exome

AF:

0.0749

Gnomad4 OTH exome

AF:

0.0811

GnomAD4 genome

AF:

0.0621

AC:

9439

AN:

152032

Hom.:

394

Cov.:

AF XY:

0.0641

AC XY:

4759

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0138

Gnomad4 AMR

AF:

0.0509

Gnomad4 ASJ

AF:

0.0948

Gnomad4 EAS

AF:

0.173

Gnomad4 SAS

AF:

0.0818

Gnomad4 FIN

AF:

0.0942

Gnomad4 NFE

AF:

0.0773

Gnomad4 OTH

AF:

0.0735

Alfa

AF:

0.0756

Hom.:

300

Bravo

AF:

0.0579

TwinsUK

AF:

0.0698

AC:

259

ALSPAC

AF:

0.0680

AC:

262

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.0836

AC:

719

ExAC

AF:

0.0783

AC:

9506

Asia WGS

AF:

0.127

AC:

443

AN:

3478

EpiCase

AF:

0.0859

EpiControl

AF:

0.0846

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4Other:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

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

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2014

GeneDx

Significance: 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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Weaver syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

.;T;.;.;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

.;D;D;D;D;D

MetaRNN

Benign

0.0016

T;T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.90

.;L;.;L;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.5

N;N;N;N;N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.011

D;D;D;D;D;D

Sift4G

Uncertain

0.017

D;D;D;D;D;D

Polyphen

0.35

B;B;P;P;B;B

Vest4

0.15

MPC

1.9

ClinPred

0.034

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.28

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

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