18-50918162-C-T

Position:

• chr18-50918162-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002396.5(ME2):​c.683C>T​(p.Thr228Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40088713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ME2	NM_002396.5	c.683C>T	p.Thr228Ile	missense_variant	7/16	ENST00000321341.11	NP_002387.1
ME2	NM_001168335.2	c.683C>T	p.Thr228Ile	missense_variant	7/14		NP_001161807.1
ME2	NR_174094.1	n.886C>T		non_coding_transcript_exon_variant	7/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11	c.683C>T	p.Thr228Ile	missense_variant	7/16	1	NM_002396.5	ENSP00000321070	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458316 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725434

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

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

May 01, 2024

The c.683C>T (p.T228I) alteration is located in exon 7 (coding exon 6) of the ME2 gene. This alteration results from a C to T substitution at nucleotide position 683, causing the threonine (T) at amino acid position 228 to be replaced by an isoleucine (I). 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	0.62
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.;.;.;.;.
Eigen	Benign	0.087
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.40	T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.5	L;.;L;.;.;.;.
MutationTaster	Benign	0.66	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.4	N;.;N;.;.;.;.
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;.;D;.;.;.;.
Sift4G	Uncertain	0.016	D;.;D;.;.;.;.
Polyphen		0.021	B;.;.;.;.;.;.
Vest4		0.19
MutPred		0.64		Loss of phosphorylation at T228 (P = 0.0243);Loss of phosphorylation at T228 (P = 0.0243);Loss of phosphorylation at T228 (P = 0.0243);Loss of phosphorylation at T228 (P = 0.0243);Loss of phosphorylation at T228 (P = 0.0243);.;.;
MVP		0.53
MPC		0.39
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.61
gMVP		0.73

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: chr18-48444532;