rs1463964154

Variant names:

• chr18-50918146-C-G
• rs1463964154
• NM_002396.5:c.667C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002396.5(ME2):​c.667C>G​(p.Gln223Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ME2 NM_002396.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3859175).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002396.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ME2	NM_002396.5	MANE Select	c.667C>G	p.Gln223Glu	missense	Exon 7 of 16	NP_002387.1	P23368-1
	ME2	NM_001168335.2		c.667C>G	p.Gln223Glu	missense	Exon 7 of 14	NP_001161807.1	P23368-2
	ME2	NR_174094.1		n.870C>G		non_coding_transcript_exon	Exon 7 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ME2	ENST00000321341.11	TSL:1 MANE Select	c.667C>G	p.Gln223Glu	missense	Exon 7 of 16	ENSP00000321070.5	P23368-1
	ME2	ENST00000382927.3	TSL:1	c.667C>G	p.Gln223Glu	missense	Exon 7 of 14	ENSP00000372384.2	P23368-2
	ME2	ENST00000901565.1		c.667C>G	p.Gln223Glu	missense	Exon 8 of 17	ENSP00000571624.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250468 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.10	T
Sift4G	Benign	0.20	T
Polyphen		0.12	B
Vest4		0.58
MutPred		0.63		Gain of ubiquitination at K224 (P = 0.0766)
MVP		0.45
MPC		0.82
ClinPred		0.58	D
GERP RS		6.0
Varity_R		0.52
gMVP		0.79
Mutation Taster		=54/46	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: rs1463964154; hg19: chr18-48444516;