rs370952608

Variant names:

• chr18-50916184-A-C
• NM_002396.5:c.409A>C

Your query was ambiguous. Multiple possible variants found:

• chr18-50916184-A-C
• chr18-50916184-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002396.5(ME2):​c.409A>C​(p.Ile137Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,036 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ME2 NM_002396.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.61

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ME2	NM_002396.5	c.409A>C	p.Ile137Leu	missense_variant	Exon 5 of 16	ENST00000321341.11	NP_002387.1
ME2	NM_001168335.2	c.409A>C	p.Ile137Leu	missense_variant	Exon 5 of 14		NP_001161807.1
ME2	NR_174094.1	n.612A>C		non_coding_transcript_exon_variant	Exon 5 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11	c.409A>C	p.Ile137Leu	missense_variant	Exon 5 of 16	1	NM_002396.5	ENSP00000321070.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459036 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725826

Gnomad4 AFR exome AF: 0.0000300

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: 0.00

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	Benign	0.14
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T;.;.;.;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L;.;L;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N;.;N;.;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.40	T;.;T;.;.;.;.
Sift4G	Benign	0.41	T;.;T;.;.;.;.
Polyphen		0.31	B;.;.;.;.;.;.
Vest4		0.76
MutPred		0.64		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MVP		0.65
MPC		1.0
ClinPred		0.87	D
GERP RS		5.8
Varity_R		0.75
gMVP		0.70

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: chr18-48442554;