rs2302427

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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 (★★). Synonymous variant affecting the same amino acid position (i.e. D185D) has been classified as Likely 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

Publications

90 publications found

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 Gene-Disease associations (from GenCC):

Weaver syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

EZH2 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 (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 VariationId is 134224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.164 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

GnomAD2 exomes

AF:

0.0783

AC:

19436

AN:

248352

AF XY:

0.0802

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 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

African (AFR)

AF:

0.0120

AC:

400

AN:

33466

American (AMR)

AF:

0.0368

AC:

1642

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0999

AC:

2608

AN:

26108

East Asian (EAS)

AF:

0.121

AC:

4808

AN:

39628

South Asian (SAS)

AF:

0.0716

AC:

6164

AN:

86128

European-Finnish (FIN)

AF:

0.0959

AC:

5113

AN:

53330

Middle Eastern (MID)

AF:

0.0911

AC:

525

AN:

5766

European-Non Finnish (NFE)

AF:

0.0749

AC:

83216

AN:

1111214

Other (OTH)

AF:

0.0811

AC:

4893

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

4834

9668

14502

19336

24170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3044

6088

9132

12176

15220

<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:

0.0621

AC:

9439

AN:

152032

Hom.:

394

Cov.:

AF XY:

0.0641

AC XY:

4759

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.0138

AC:

573

AN:

41484

American (AMR)

AF:

0.0509

AC:

778

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0948

AC:

329

AN:

3472

East Asian (EAS)

AF:

0.173

AC:

893

AN:

5164

South Asian (SAS)

AF:

0.0818

AC:

393

AN:

4806

European-Finnish (FIN)

AF:

0.0942

AC:

993

AN:

10538

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0773

AC:

5251

AN:

67974

Other (OTH)

AF:

0.0735

AC:

155

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

447

895

1342

1790

2237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0756

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

- -

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. -

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

- -

Weaver syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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;.;.

PhyloP100

7.3

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

Mutation Taster

=89/11

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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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