NM_006709.5:c.2207A>G

Variant names:

• chr6-31886809-T-C
• NM_006709.5:c.2207A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006709.5(EHMT2):​c.2207A>G​(p.Tyr736Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EHMT2 NM_006709.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78
• Publications: 0 publications found

Genes affected

EHMT2 (HGNC:14129): (euchromatic histone lysine methyltransferase 2) This gene encodes a methyltransferase that methylates lysine residues of histone H3. Methylation of H3 at lysine 9 by this protein results in recruitment of additional epigenetic regulators and repression of transcription. This gene was initially thought to be two different genes, NG36 and G9a, adjacent to each other in the HLA locus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

EHMT2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006709.5. 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
	EHMT2	NM_006709.5	MANE Select	c.2207A>G	p.Tyr736Cys	missense	Exon 17 of 28	NP_006700.3
	EHMT2	NM_001363689.2		c.2378A>G	p.Tyr793Cys	missense	Exon 16 of 27	NP_001350618.1	A2ABF9
	EHMT2	NM_001289413.2		c.2276A>G	p.Tyr759Cys	missense	Exon 15 of 26	NP_001276342.1	A2ABF8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT2	ENST00000375537.9	TSL:1 MANE Select	c.2207A>G	p.Tyr736Cys	missense	Exon 17 of 28	ENSP00000364687.4	Q96KQ7-1
	EHMT2	ENST00000395728.7	TSL:1	c.2378A>G	p.Tyr793Cys	missense	Exon 16 of 27	ENSP00000379078.3	A2ABF9
	EHMT2	ENST00000962959.1		c.2207A>G	p.Tyr736Cys	missense	Exon 17 of 29	ENSP00000633018.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.0089	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.016	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.66		Gain of catalytic residue at V761 (P = 0.0847)
MVP		0.85
MPC		2.3
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.80
Mutation Taster		=38/62	disease causing

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

hg19: chr6-31854586;