18-50916219-T-A

Position:

• chr18-50916219-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002396.5(ME2):​c.444T>A​(p.Asp148Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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: 0.700

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24449596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ME2	NM_002396.5	c.444T>A	p.Asp148Glu	missense_variant	5/16	ENST00000321341.11	NP_002387.1
ME2	NM_001168335.2	c.444T>A	p.Asp148Glu	missense_variant	5/14		NP_001161807.1
ME2	NR_174094.1	n.647T>A		non_coding_transcript_exon_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11	c.444T>A	p.Asp148Glu	missense_variant	5/16	1	NM_002396.5	ENSP00000321070.5

Frequencies

GnomAD3 genomes Cov.: 32

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.444T>A (p.D148E) alteration is located in exon 5 (coding exon 4) of the ME2 gene. This alteration results from a T to A substitution at nucleotide position 444, causing the aspartic acid (D) at amino acid position 148 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	0.18
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;.;.;.;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D;D;T;T;T;D;D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.24	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.40	N;.;N;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.21	N;.;N;.;.;.;.
REVEL	Benign	0.089
Sift	Benign	0.099	T;.;T;.;.;.;.
Sift4G	Benign	0.40	T;.;T;.;.;.;.
Polyphen		0.0	B;.;.;.;.;.;.
Vest4		0.24
MutPred		0.29		Gain of disorder (P = 0.1646);Gain of disorder (P = 0.1646);Gain of disorder (P = 0.1646);Gain of disorder (P = 0.1646);Gain of disorder (P = 0.1646);Gain of disorder (P = 0.1646);.;
MVP		0.55
MPC		0.30
ClinPred		0.65	D
GERP RS		4.6
Varity_R		0.38
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-48442589;