18-50921075-C-A

Variant names:

• chr18-50921075-C-A
• NM_002396.5:c.944C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002396.5(ME2):​c.944C>A​(p.Ala315Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ME2 NM_002396.5 missense, splice_region
• Scores: Splicing: ADA: 0.9918
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.944C>A	p.Ala315Asp	missense splice_region	Exon 10 of 16	NP_002387.1	P23368-1
	ME2	NM_001168335.2		c.944C>A	p.Ala315Asp	missense splice_region	Exon 10 of 14	NP_001161807.1	P23368-2
	ME2	NR_174094.1		n.1147C>A		splice_region non_coding_transcript_exon	Exon 10 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ME2	ENST00000321341.11	TSL:1 MANE Select	c.944C>A	p.Ala315Asp	missense splice_region	Exon 10 of 16	ENSP00000321070.5	P23368-1
	ME2	ENST00000382927.3	TSL:1	c.944C>A	p.Ala315Asp	missense splice_region	Exon 10 of 14	ENSP00000372384.2	P23368-2
	ME2	ENST00000901565.1		c.944C>A	p.Ala315Asp	missense splice_region	Exon 11 of 17	ENSP00000571624.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.32e-7 AC: 1 AN: 1365582 Hom.: 0 Cov.: 23 AF XY: 0.00000147 AC XY: 1 AN XY: 682528

⚠️ 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: 29648

American (AMR) AF: 0.00 AC: 0 AN: 33860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24094

East Asian (EAS) AF: 0.00 AC: 0 AN: 37870

South Asian (SAS) AF: 0.00 AC: 0 AN: 77146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5494

European-Non Finnish (NFE) AF: 9.54e-7 AC: 1 AN: 1048178

Other (OTH) AF: 0.00 AC: 0 AN: 56668

⚠️ 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

ClinVar submissions

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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		7.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.90		Loss of catalytic residue at G313 (P = 0.1205)
MVP		0.91
MPC		1.3
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.84
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

hg19: chr18-48447445;