7-148807690-C-CATCAGCCT

Variant names:

• chr7-148807690-C-CATCAGCCT
• rs2129465354
• NM_004456.5:c.2204_2211dupAGGCTGAT

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_004456.5(EZH2):​c.2204_2211dupAGGCTGAT​(p.Ala738ArgfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: EZH2 NM_004456.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.585
• Publications: 1 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-148807690-C-CATCAGCCT is Pathogenic according to our data. Variant chr7-148807690-C-CATCAGCCT is described in ClinVar as Pathogenic. ClinVar VariationId is 1700628.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.2204_2211dupAGGCTGAT	p.Ala738ArgfsTer5	frameshift	Exon 20 of 20	NP_004447.2
	EZH2	NM_001203247.2		c.2189_2196dupAGGCTGAT	p.Ala733ArgfsTer5	frameshift	Exon 20 of 20	NP_001190176.1	Q15910-1
	EZH2	NM_001203248.2		c.2162_2169dupAGGCTGAT	p.Ala724ArgfsTer5	frameshift	Exon 20 of 20	NP_001190177.1	Q15910-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.2204_2211dupAGGCTGAT	p.Ala738ArgfsTer5	frameshift	Exon 20 of 20	ENSP00000320147.2	Q15910-2
	EZH2	ENST00000460911.5	TSL:1	c.2189_2196dupAGGCTGAT	p.Ala733ArgfsTer5	frameshift	Exon 20 of 20	ENSP00000419711.1	Q15910-1
	EZH2	ENST00000350995.6	TSL:1	c.2072_2079dupAGGCTGAT	p.Ala694ArgfsTer5	frameshift	Exon 19 of 19	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Weaver syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.58
Mutation Taster		=0/200	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2129465354; hg19: chr7-148504782;