chr18-50932292-G-A

Position:

• chr18-50932292-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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 (★). 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 criteria provided, single submitter 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]

ACMG classification

Verdict is Benign. Variant got -14 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 criteria_provided_single_submitter, 1 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	UniProt
ME2	NM_002396.5	c.1349G>A	p.Gly450Glu	missense_variant	13/16	ENST00000321341.11
ME2	NM_001168335.2	c.1349G>A	p.Gly450Glu	missense_variant	13/14
ME2	NR_174094.1	n.1552G>A		non_coding_transcript_exon_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ME2	ENST00000321341.11	c.1349G>A	p.Gly450Glu	missense_variant	13/16	1	NM_002396.5	P1

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: criteria provided, single submitter

Submissions by phenotype

ME2-related disorder Benign:1

Benign, criteria provided, single submitter

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;.;.;.;.
MutationTaster	Benign	0.99	P;P
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;