Variant 18-50918146-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002396.5(ME2):c.667C>G(p.Gln223Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ME2
NM_002396.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.70

Variant links:

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 links:

ME2 (HGNC:):

ME2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3859175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ME2	NM_002396.5 linkuse as main transcript	c.667C>G	p.Gln223Glu	missense_variant	7/16	ENST00000321341.11	NP_002387.1	P23368-1
ME2	NM_001168335.2 linkuse as main transcript	c.667C>G	p.Gln223Glu	missense_variant	7/14		NP_001161807.1	P23368-2
ME2	NR_174094.1 linkuse as main transcript	n.870C>G		non_coding_transcript_exon_variant	7/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11 linkuse as main transcript	c.667C>G	p.Gln223Glu	missense_variant	7/16	1	NM_002396.5	ENSP00000321070.5		P23368-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250468

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135404

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.667C>G (p.Q223E) alteration is located in exon 7 (coding exon 6) of the ME2 gene. This alteration results from a C to G substitution at nucleotide position 667, causing the glutamine (Q) at amino acid position 223 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.050

T;.;.;.;.;.;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.39

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;.;L;.;.;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.4

N;.;N;.;.;.;.

REVEL

Benign

0.12

Sift

Benign

0.10

T;.;T;.;.;.;.

Sift4G

Benign

0.20

T;.;T;.;.;.;.

Polyphen

0.12

B;.;.;.;.;.;.

Vest4

0.58

MutPred

0.63

Gain of ubiquitination at K224 (P = 0.0766);Gain of ubiquitination at K224 (P = 0.0766);Gain of ubiquitination at K224 (P = 0.0766);Gain of ubiquitination at K224 (P = 0.0766);Gain of ubiquitination at K224 (P = 0.0766);.;.;

MVP

0.45

MPC

0.82

ClinPred

0.58

GERP RS

6.0

Varity_R

0.52

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over