7-148808368-G-C

Variant names:

• chr7-148808368-G-C
• rs734004
• NM_004456.5:c.2196-662C>G

Variant summary

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

The NM_004456.5(EZH2):​c.2196-662C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 152,190 control chromosomes in the GnomAD database, including 33,209 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 0.66 (33209 hom., cov: 34)
• Consequence: EZH2 NM_004456.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.252
• Publications: 9 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.2196-662C>G		intron	N/A	NP_004447.2
	EZH2	NM_001203247.2		c.2181-662C>G		intron	N/A	NP_001190176.1
	EZH2	NM_001203248.2		c.2154-662C>G		intron	N/A	NP_001190177.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.2196-662C>G		intron	N/A	ENSP00000320147.2
	EZH2	ENST00000460911.5	TSL:1	c.2181-662C>G		intron	N/A	ENSP00000419711.1
	EZH2	ENST00000350995.6	TSL:1	c.2064-662C>G		intron	N/A	ENSP00000223193.2

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99812 AN: 152070 Hom.: 33185 Cov.: 34

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.674

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.614

Gnomad OTH AF: 0.636

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

GnomAD4 genome AF: 0.656 AC: 99892 AN: 152190 Hom.: 33209 Cov.: 34 AF XY: 0.654 AC XY: 48636 AN XY: 74376

African (AFR) AF: 0.758 AC: 31475 AN: 41538

American (AMR) AF: 0.675 AC: 10326 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2029 AN: 3472

East Asian (EAS) AF: 0.667 AC: 3451 AN: 5172

South Asian (SAS) AF: 0.610 AC: 2937 AN: 4818

European-Finnish (FIN) AF: 0.553 AC: 5843 AN: 10570

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.614 AC: 41773 AN: 67998

Other (OTH) AF: 0.637 AC: 1346 AN: 2112

Alfa AF: 0.629 Hom.: 3766

Bravo AF: 0.672

Asia WGS AF: 0.655 AC: 2277 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.69
DANN	Benign	0.43
PhyloP100		-0.25
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: rs734004; hg19: chr7-148505460;