18-50932292-G-T

Variant names:

• chr18-50932292-G-T
• rs649224
• NM_002396.5:c.1349G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002396.5(ME2):​c.1349G>T​(p.Gly450Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,902 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G450E) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ME2 NM_002396.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.287
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 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.1349G>T	p.Gly450Val	missense_variant	Exon 13 of 16	ENST00000321341.11	NP_002387.1
ME2	NM_001168335.2	c.1349G>T	p.Gly450Val	missense_variant	Exon 13 of 14		NP_001161807.1
ME2	NR_174094.1	n.1552G>T		non_coding_transcript_exon_variant	Exon 13 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11	c.1349G>T	p.Gly450Val	missense_variant	Exon 13 of 16	1	NM_002396.5	ENSP00000321070.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459902 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726298

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 86012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110772

Other (OTH) AF: 0.00 AC: 0 AN: 60288

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.099	T;.;.;.;.;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L;.;L;.;.;.;.
PhyloP100		0.29
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N;.;N;.;.;.;.
REVEL	Benign	0.072
Sift	Benign	0.057	T;.;T;.;.;.;.
Sift4G	Benign	0.10	T;.;T;.;.;.;.
Polyphen		0.068	B;.;.;.;.;.;.
Vest4		0.31
MutPred		0.48		Loss of ubiquitination at K453 (P = 0.0456);Loss of ubiquitination at K453 (P = 0.0456);Loss of ubiquitination at K453 (P = 0.0456);.;Loss of ubiquitination at K453 (P = 0.0456);.;.;
MVP		0.33
MPC		0.50
ClinPred		0.24	T
GERP RS		-4.5
Varity_R		0.36
gMVP		0.82
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs649224; hg19: chr18-48458662;