rs649224

Positions:

• chr18-50932292-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002396.5(ME2):​c.1349G>A​(p.Gly450Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.09 in 1,611,000 control chromosomes in the GnomAD database, including 8,917 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (2305 hom., cov: 32)
  • Exomes 𝑓: 0.085 (6612 hom.)
• Consequence: ME2 NM_002396.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.287

Genes affected

ME2 (HGNC:6984): (malic enzyme 2) This gene encodes a mitochondrial NAD-dependent malic enzyme, a homotetrameric protein, that catalyzes the oxidative decarboxylation of malate to pyruvate. It had previously been weakly linked to a syndrome known as Friedreich ataxia that has since been shown to be the result of mutation in a completely different gene. Certain single-nucleotide polymorphism haplotypes of this gene have been shown to increase the risk for idiopathic generalized epilepsy. Alternatively spliced transcript variants encoding different isoforms found for this gene. [provided by RefSeq, Dec 2009]

ME2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028408766).
• BP6: Variant 18-50932292-G-A is Benign according to our data. Variant chr18-50932292-G-A is described in ClinVar as [Benign]. Clinvar id is 3060471.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ME2	NM_002396.5	c.1349G>A	p.Gly450Glu	missense_variant	13/16	ENST00000321341.11	NP_002387.1
ME2	NM_001168335.2	c.1349G>A	p.Gly450Glu	missense_variant	13/14		NP_001161807.1
ME2	NR_174094.1	n.1552G>A		non_coding_transcript_exon_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11	c.1349G>A	p.Gly450Glu	missense_variant	13/16	1	NM_002396.5	ENSP00000321070.5

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21456 AN: 151886 Hom.: 2296 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0998

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.0986

Gnomad SAS AF: 0.0937

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.140

GnomAD3 exomes AF: 0.0924 AC: 23139 AN: 250408 Hom.: 1576 AF XY: 0.0904 AC XY: 12238 AN XY: 135336

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.0630

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.0881

Gnomad SAS exome AF: 0.0953

Gnomad FIN exome AF: 0.0568

Gnomad NFE exome AF: 0.0738

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0846 AC: 123447 AN: 1458996 Hom.: 6612 Cov.: 30 AF XY: 0.0848 AC XY: 61533 AN XY: 725864

Gnomad4 AFR exome AF: 0.325

Gnomad4 AMR exome AF: 0.0677

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.124

Gnomad4 SAS exome AF: 0.0947

Gnomad4 FIN exome AF: 0.0583

Gnomad4 NFE exome AF: 0.0747

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.141 AC: 21505 AN: 152004 Hom.: 2305 Cov.: 32 AF XY: 0.140 AC XY: 10421 AN XY: 74334

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.0996

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.0988

Gnomad4 SAS AF: 0.0942

Gnomad4 FIN AF: 0.0587

Gnomad4 NFE AF: 0.0734

Gnomad4 OTH AF: 0.139

Alfa AF: 0.114 Hom.: 798

Bravo AF: 0.151

TwinsUK AF: 0.0868 AC: 322

ALSPAC AF: 0.0727 AC: 280

ESP6500AA AF: 0.285 AC: 1257

ESP6500EA AF: 0.0769 AC: 661

ExAC AF: 0.0970 AC: 11783

Asia WGS AF: 0.0970 AC: 340 AN: 3474

EpiCase AF: 0.0802

EpiControl AF: 0.0812

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ME2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.9
DANN	Benign	0.79
DEOGEN2	Benign	0.017	T;.;.;.;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.81	T;T;T;T;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.74	N;.;N;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.46	N;.;N;.;.;.;.
REVEL	Benign	0.039
Sift	Benign	0.42	T;.;T;.;.;.;.
Sift4G	Benign	0.56	T;.;T;.;.;.;.
Polyphen		0.0	B;.;.;.;.;.;.
Vest4		0.037
MPC		0.39
ClinPred		0.00073	T
GERP RS		-4.5
Varity_R		0.066
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs649224; hg19: chr18-48458662; COSMIC: COSV58422758;