chr18-50895906-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002396.5(ME2):ā€‹c.86T>Cā€‹(p.Met29Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000199 in 1,460,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.000020 ( 0 hom. )

Consequence

ME2
NM_002396.5 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.51
Variant links:
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27053717).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ME2NM_002396.5 linkuse as main transcriptc.86T>C p.Met29Thr missense_variant 2/16 ENST00000321341.11
ME2NM_001168335.2 linkuse as main transcriptc.86T>C p.Met29Thr missense_variant 2/14
ME2NR_174094.1 linkuse as main transcriptn.289T>C non_coding_transcript_exon_variant 2/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ME2ENST00000321341.11 linkuse as main transcriptc.86T>C p.Met29Thr missense_variant 2/161 NM_002396.5 P1P23368-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251126
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135762
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000199
AC:
29
AN:
1460802
Hom.:
0
Cov.:
29
AF XY:
0.0000193
AC XY:
14
AN XY:
726782
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000252
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 submitterclinical testingAmbry GeneticsSep 29, 2022The c.86T>C (p.M29T) alteration is located in exon 2 (coding exon 1) of the ME2 gene. This alteration results from a T to C substitution at nucleotide position 86, causing the methionine (M) at amino acid position 29 to be replaced by a threonine (T). 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
Pathogenic
0.65
BayesDel_addAF
Benign
-0.010
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
19
DANN
Benign
0.96
DEOGEN2
Benign
0.041
T;.;.;.;.;.
Eigen
Benign
-0.026
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.87
D;D;D;T;D;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.27
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;.;L;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-1.7
N;.;N;.;.;.
REVEL
Benign
0.14
Sift
Benign
0.17
T;.;T;.;.;.
Sift4G
Benign
0.10
T;.;T;.;.;.
Polyphen
0.0020
B;.;.;.;.;.
Vest4
0.78
MutPred
0.55
Gain of phosphorylation at M29 (P = 0.0582);Gain of phosphorylation at M29 (P = 0.0582);Gain of phosphorylation at M29 (P = 0.0582);Gain of phosphorylation at M29 (P = 0.0582);Gain of phosphorylation at M29 (P = 0.0582);Gain of phosphorylation at M29 (P = 0.0582);
MVP
0.42
MPC
0.99
ClinPred
0.33
T
GERP RS
6.1
Varity_R
0.54
gMVP
0.86

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776851081; hg19: chr18-48422276; API