18-50918146-C-G

Variant names:

• chr18-50918146-C-G
• rs1463964154
• NM_002396.5:c.667C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70

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 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 rank	MANE	Protein	UniProt
ME2	NM_002396.5	c.667C>G	p.Gln223Glu	missense_variant	Exon 7 of 16	ENST00000321341.11	NP_002387.1
ME2	NM_001168335.2	c.667C>G	p.Gln223Glu	missense_variant	Exon 7 of 14		NP_001161807.1
ME2	NR_174094.1	n.870C>G		non_coding_transcript_exon_variant	Exon 7 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11	c.667C>G	p.Gln223Glu	missense_variant	Exon 7 of 16	1	NM_002396.5	ENSP00000321070.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250468 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135404

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.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T;.;.;.;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.39	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;L;.;.;.;.
PrimateAI	Uncertain	0.67	T
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	D
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

Other links and lift over

dbSNP: rs1463964154; hg19: chr18-48444516;