18-50920751-C-A

Variant names:

• chr18-50920751-C-A
• rs767927111
• NM_002396.5:c.935C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002396.5(ME2):​c.935C>A​(p.Ala312Glu) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ME2 NM_002396.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.90

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ME2	NM_002396.5	c.935C>A	p.Ala312Glu	missense_variant	Exon 9 of 16	ENST00000321341.11	NP_002387.1
ME2	NM_001168335.2	c.935C>A	p.Ala312Glu	missense_variant	Exon 9 of 14		NP_001161807.1
ME2	NR_174094.1	n.1138C>A		non_coding_transcript_exon_variant	Exon 9 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11	c.935C>A	p.Ala312Glu	missense_variant	Exon 9 of 16	1	NM_002396.5	ENSP00000321070.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.;.;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	4.0	H;.;H;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.9	D;.;D;.;.;.;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;.;D;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.98
MutPred		0.92		Loss of catalytic residue at A312 (P = 0.1981);Loss of catalytic residue at A312 (P = 0.1981);Loss of catalytic residue at A312 (P = 0.1981);Loss of catalytic residue at A312 (P = 0.1981);Loss of catalytic residue at A312 (P = 0.1981);.;.;
MVP		0.90
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.96

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: rs767927111; hg19: chr18-48447121;