18-50919433-T-C

Variant names:

• chr18-50919433-T-C
• rs685533
• NM_002396.5:c.735-1023T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002396.5(ME2):​c.735-1023T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 151,962 control chromosomes in the GnomAD database, including 35,880 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.68 (35880 hom., cov: 31)
• Consequence: ME2 NM_002396.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.418
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ME2	NM_002396.5	MANE Select	c.735-1023T>C		intron	N/A	NP_002387.1
	ME2	NM_001168335.2		c.735-1023T>C		intron	N/A	NP_001161807.1
	ME2	NR_174094.1		n.938-1023T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ME2	ENST00000321341.11	TSL:1 MANE Select	c.735-1023T>C		intron	N/A	ENSP00000321070.5
	ME2	ENST00000382927.3	TSL:1	c.735-1023T>C		intron	N/A	ENSP00000372384.2
	ME2	ENST00000901565.1		c.735-1023T>C		intron	N/A	ENSP00000571624.1

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103715 AN: 151844 Hom.: 35841 Cov.: 31

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.783

Gnomad FIN AF: 0.557

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.695

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.683 AC: 103810 AN: 151962 Hom.: 35880 Cov.: 31 AF XY: 0.684 AC XY: 50804 AN XY: 74252

African (AFR) AF: 0.786 AC: 32592 AN: 41462

American (AMR) AF: 0.750 AC: 11455 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 2256 AN: 3470

East Asian (EAS) AF: 0.658 AC: 3392 AN: 5156

South Asian (SAS) AF: 0.783 AC: 3779 AN: 4826

European-Finnish (FIN) AF: 0.557 AC: 5876 AN: 10546

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.624 AC: 42381 AN: 67920

Other (OTH) AF: 0.691 AC: 1460 AN: 2114

Alfa AF: 0.661 Hom.: 4363

Bravo AF: 0.697

Asia WGS AF: 0.704 AC: 2450 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.5
DANN	Benign	0.44
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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: rs685533; hg19: chr18-48445803;