chr18-50917353-G-T

Variant names:

• chr18-50917353-G-T
• NM_002396.5:c.475G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002396.5(ME2):​c.475G>T​(p.Val159Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,368 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ME2 NM_002396.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.32

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ME2	NM_002396.5	c.475G>T	p.Val159Leu	missense_variant	Exon 6 of 16	ENST00000321341.11	NP_002387.1
ME2	NM_001168335.2	c.475G>T	p.Val159Leu	missense_variant	Exon 6 of 14		NP_001161807.1
ME2	NR_174094.1	n.678G>T		non_coding_transcript_exon_variant	Exon 6 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11	c.475G>T	p.Val159Leu	missense_variant	Exon 6 of 16	1	NM_002396.5	ENSP00000321070.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460368 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D
MetaSVM	Uncertain	0.00020	D
MutationAssessor	Pathogenic	3.0	M;.;M;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N;.;N;.;.;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D;.;D;.;.;.
Sift4G	Uncertain	0.0080	D;.;D;.;.;.
Polyphen		0.94	P;.;.;.;.;.
Vest4		0.62
MutPred		0.76		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;
MVP		0.71
MPC		0.39
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.92
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-48443723;