18-50920751-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_002396.5(ME2):c.935C>T(p.Ala312Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ME2
NM_002396.5 missense
NM_002396.5 missense
Scores
11
6
2
Clinical Significance
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
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, 0.976
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ME2 | NM_002396.5 | c.935C>T | p.Ala312Val | missense_variant | 9/16 | ENST00000321341.11 | NP_002387.1 | |
ME2 | NM_001168335.2 | c.935C>T | p.Ala312Val | missense_variant | 9/14 | NP_001161807.1 | ||
ME2 | NR_174094.1 | n.1138C>T | non_coding_transcript_exon_variant | 9/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ME2 | ENST00000321341.11 | c.935C>T | p.Ala312Val | missense_variant | 9/16 | 1 | NM_002396.5 | ENSP00000321070.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000821 AC: 2AN: 243568Hom.: 0 AF XY: 0.00000758 AC XY: 1AN XY: 131886
GnomAD3 exomes
AF:
AC:
2
AN:
243568
Hom.:
AF XY:
AC XY:
1
AN XY:
131886
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1451610Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1AN XY: 722024
GnomAD4 exome
AF:
AC:
2
AN:
1451610
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
722024
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
Bravo
AF:
ExAC
AF:
AC:
1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 29, 2024 | The c.935C>T (p.A312V) alteration is located in exon 9 (coding exon 8) of the ME2 gene. This alteration results from a C to T substitution at nucleotide position 935, causing the alanine (A) at amino acid position 312 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;M;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;.;.;.;.
Sift4G
Uncertain
D;.;D;.;.;.;.
Polyphen
D;.;.;.;.;.;.
Vest4
MutPred
Loss of sheet (P = 0.3635);Loss of sheet (P = 0.3635);Loss of sheet (P = 0.3635);Loss of sheet (P = 0.3635);Loss of sheet (P = 0.3635);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at