NM_004456.5:c.2195+299C>T

Variant names:

• chr7-148808772-G-A
• rs734005
• NM_004456.5:c.2195+299C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004456.5(EZH2):​c.2195+299C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 152,122 control chromosomes in the GnomAD database, including 38,442 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 0.70 (38442 hom., cov: 32)
• Consequence: EZH2 NM_004456.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.99
• Publications: 6 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.895 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5	c.2195+299C>T		intron_variant	Intron 19 of 19	ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.2195+299C>T		intron_variant	Intron 19 of 19	1	NM_004456.5	ENSP00000320147.2

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106112 AN: 152004 Hom.: 38393 Cov.: 32

Gnomad AFR AF: 0.903

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.688

Gnomad ASJ AF: 0.587

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.615

Gnomad OTH AF: 0.665

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

GnomAD4 genome AF: 0.698 AC: 106223 AN: 152122 Hom.: 38442 Cov.: 32 AF XY: 0.695 AC XY: 51679 AN XY: 74358

African (AFR) AF: 0.903 AC: 37495 AN: 41516

American (AMR) AF: 0.689 AC: 10536 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 2036 AN: 3470

East Asian (EAS) AF: 0.669 AC: 3454 AN: 5166

South Asian (SAS) AF: 0.610 AC: 2940 AN: 4818

European-Finnish (FIN) AF: 0.554 AC: 5845 AN: 10558

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.615 AC: 41797 AN: 67984

Other (OTH) AF: 0.666 AC: 1408 AN: 2114

Alfa AF: 0.526 Hom.: 1489

Bravo AF: 0.719

Asia WGS AF: 0.668 AC: 2324 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.33
DANN	Benign	0.63
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs734005; hg19: chr7-148505864;