6-31896770-G-T

Variant names:

• chr6-31896770-G-T
• rs7887
• NM_006709.5:c.164C>A

Variant summary

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

The NM_006709.5(EHMT2):​c.164C>A​(p.Thr55Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,612,788 control chromosomes in the GnomAD database, including 103,389 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (8483 hom., cov: 32)
  • Exomes 𝑓: 0.35 (94906 hom.)
• Consequence: EHMT2 NM_006709.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33
• Publications: 48 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.5850968E-5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT2	NM_006709.5	MANE Select	c.164C>A	p.Thr55Asn	missense	Exon 3 of 28	NP_006700.3
	EHMT2	NM_001363689.2		c.335C>A	p.Thr112Asn	missense	Exon 2 of 27	NP_001350618.1
	EHMT2	NM_001289413.2		c.335C>A	p.Thr112Asn	missense	Exon 2 of 26	NP_001276342.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT2	ENST00000375537.9	TSL:1 MANE Select	c.164C>A	p.Thr55Asn	missense	Exon 3 of 28	ENSP00000364687.4
	EHMT2	ENST00000395728.7	TSL:1	c.335C>A	p.Thr112Asn	missense	Exon 2 of 27	ENSP00000379078.3
	EHMT2	ENST00000375528.8	TSL:2	c.335C>A	p.Thr112Asn	missense	Exon 2 of 26	ENSP00000364678.4

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45038 AN: 152018 Hom.: 8470 Cov.: 32

Gnomad AFR AF: 0.0763

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.549

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.301

GnomAD2 exomes AF: 0.395 AC: 96900 AN: 245270 AF XY: 0.391

Gnomad AFR exome AF: 0.0691

Gnomad AMR exome AF: 0.592

Gnomad ASJ exome AF: 0.514

Gnomad EAS exome AF: 0.558

Gnomad FIN exome AF: 0.351

Gnomad NFE exome AF: 0.367

Gnomad OTH exome AF: 0.375

GnomAD4 exome AF: 0.349 AC: 510309 AN: 1460650 Hom.: 94906 Cov.: 55 AF XY: 0.351 AC XY: 255068 AN XY: 726648

African (AFR) AF: 0.0632 AC: 2117 AN: 33480

American (AMR) AF: 0.570 AC: 25502 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.502 AC: 13124 AN: 26126

East Asian (EAS) AF: 0.625 AC: 24806 AN: 39698

South Asian (SAS) AF: 0.336 AC: 29000 AN: 86256

European-Finnish (FIN) AF: 0.342 AC: 17891 AN: 52300

Middle Eastern (MID) AF: 0.388 AC: 2239 AN: 5768

European-Non Finnish (NFE) AF: 0.338 AC: 375384 AN: 1111930

Other (OTH) AF: 0.335 AC: 20246 AN: 60382

GnomAD4 genome AF: 0.296 AC: 45057 AN: 152138 Hom.: 8483 Cov.: 32 AF XY: 0.301 AC XY: 22418 AN XY: 74358

African (AFR) AF: 0.0761 AC: 3164 AN: 41560

American (AMR) AF: 0.457 AC: 6989 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 1778 AN: 3468

East Asian (EAS) AF: 0.549 AC: 2828 AN: 5148

South Asian (SAS) AF: 0.355 AC: 1708 AN: 4816

European-Finnish (FIN) AF: 0.342 AC: 3623 AN: 10586

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23798 AN: 67958

Other (OTH) AF: 0.302 AC: 637 AN: 2106

Alfa AF: 0.329 Hom.: 15544

Bravo AF: 0.298

TwinsUK AF: 0.343 AC: 1270

ALSPAC AF: 0.323 AC: 1246

ESP6500AA AF: 0.0927 AC: 280

ESP6500EA AF: 0.348 AC: 1888

ExAC AF: 0.382 AC: 44783

Asia WGS AF: 0.377 AC: 1315 AN: 3478

EpiCase AF: 0.378

EpiControl AF: 0.388

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.40
DANN	Benign	0.49
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.051	N
MetaRNN	Benign	0.000046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.057
Sift	Benign	1.0	T
Sift4G	Uncertain	0.047	D
Polyphen		0.0	B
Vest4		0.0070
MPC		0.56
ClinPred		0.0039	T
GERP RS		-6.0
PromoterAI		0.0049	Neutral
Varity_R		0.031
gMVP		0.052
Mutation Taster		=95/5	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: rs7887; hg19: chr6-31864547; COSMIC: COSV64994251; COSMIC: COSV64994251;