rs765936779

Variant names:

• chr6-31886812-C-T
• rs765936779
• NM_006709.5:c.2204G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006709.5(EHMT2):​c.2204G>A​(p.Arg735His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: EHMT2 NM_006709.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.395
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35665917).

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.2204G>A	p.Arg735His	missense	Exon 17 of 28	NP_006700.3
	EHMT2	NM_001363689.2		c.2375G>A	p.Arg792His	missense	Exon 16 of 27	NP_001350618.1	A2ABF9
	EHMT2	NM_001289413.2		c.2273G>A	p.Arg758His	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.2204G>A	p.Arg735His	missense	Exon 17 of 28	ENSP00000364687.4	Q96KQ7-1
	EHMT2	ENST00000395728.7	TSL:1	c.2375G>A	p.Arg792His	missense	Exon 16 of 27	ENSP00000379078.3	A2ABF9
	EHMT2	ENST00000962959.1		c.2204G>A	p.Arg735His	missense	Exon 17 of 29	ENSP00000633018.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251476 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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	Benign	0.088
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.011
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.24	N
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.40
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.30
Sift	Benign	0.051	T
Sift4G	Uncertain	0.012	D
Polyphen		0.74	P
Vest4		0.45
MutPred		0.59		Loss of MoRF binding (P = 0.0654)
MVP		0.72
MPC		1.2
ClinPred		0.90	D
GERP RS		5.4
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.44
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs765936779; hg19: chr6-31854589; COSMIC: COSV64998170; COSMIC: COSV64998170;