Genetic Variant EZH2:c.2196-504G>A (chr7-148808210-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004456.5(EZH2):c.2196-504G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 152,198 control chromosomes in the GnomAD database, including 40,353 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.73 ( 40353 hom., cov: 33)

Consequence

EZH2
NM_004456.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.627

Publications

12 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

EZH2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004456.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EZH2	NM_004456.5	MANE Select	c.2196-504G>A	intron	N/A	NP_004447.2
EZH2	NM_001203247.2		c.2181-504G>A	intron	N/A	NP_001190176.1	Q15910-1
EZH2	NM_001203248.2		c.2154-504G>A	intron	N/A	NP_001190177.1	Q15910-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EZH2	ENST00000320356.7	TSL:1 MANE Select	c.2196-504G>A	intron	N/A	ENSP00000320147.2	Q15910-2
EZH2	ENST00000460911.5	TSL:1	c.2181-504G>A	intron	N/A	ENSP00000419711.1	Q15910-1
EZH2	ENST00000350995.6	TSL:1	c.2064-504G>A	intron	N/A	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes

AF:

0.726

AC:

110473

AN:

152080

Hom.:

40329

Cov.:

show subpopulations

Gnomad AFR

AF:

0.775

Gnomad AMI

AF:

0.601

Gnomad AMR

AF:

0.760

Gnomad ASJ

AF:

0.725

Gnomad EAS

AF:

0.671

Gnomad SAS

AF:

0.634

Gnomad FIN

AF:

0.644

Gnomad MID

AF:

0.763

Gnomad NFE

AF:

0.715

Gnomad OTH

AF:

0.720

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.726

AC:

110553

AN:

152198

Hom.:

40353

Cov.:

AF XY:

0.722

AC XY:

53726

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.775

AC:

32190

AN:

41548

American (AMR)

AF:

0.760

AC:

11623

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.725

AC:

2517

AN:

3472

East Asian (EAS)

AF:

0.670

AC:

3470

AN:

5178

South Asian (SAS)

AF:

0.635

AC:

3064

AN:

4824

European-Finnish (FIN)

AF:

0.644

AC:

6818

AN:

10580

Middle Eastern (MID)

AF:

0.762

AC:

224

AN:

294

European-Non Finnish (NFE)

AF:

0.715

AC:

48578

AN:

67982

Other (OTH)

AF:

0.720

AC:

1521

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1564

3129

4693

6258

7822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.717

Hom.:

10593

Bravo

AF:

0.739

Asia WGS

AF:

0.671

AC:

2333

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.69

(source)

DANN

Benign

0.44

PhyloP100

-0.63

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over