18-50925937-C-T

Variant names:

• chr18-50925937-C-T
• rs1397266
• NM_002396.5:c.1314+39C>T

Variant summary

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

The NM_002396.5(ME2):​c.1314+39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0612 in 1,425,626 control chromosomes in the GnomAD database, including 3,078 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 0.048 (259 hom., cov: 32)
  • Exomes 𝑓: 0.063 (2819 hom.)
• Consequence: ME2 NM_002396.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.721
• Publications: 5 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ME2	NM_002396.5	c.1314+39C>T		intron_variant	Intron 12 of 15	ENST00000321341.11	NP_002387.1
ME2	NM_001168335.2	c.1314+39C>T		intron_variant	Intron 12 of 13		NP_001161807.1
ME2	NR_174094.1	n.1517+39C>T		intron_variant	Intron 12 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11	c.1314+39C>T		intron_variant	Intron 12 of 15	1	NM_002396.5	ENSP00000321070.5

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7341 AN: 152078 Hom.: 259 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0500

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.0753

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0712

Gnomad OTH AF: 0.0602

GnomAD2 exomes AF: 0.0492 AC: 11219 AN: 228196 AF XY: 0.0497

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.0339

Gnomad EAS exome AF: 0.000234

Gnomad FIN exome AF: 0.0719

Gnomad NFE exome AF: 0.0713

Gnomad OTH exome AF: 0.0601

GnomAD4 exome AF: 0.0628 AC: 79937 AN: 1273430 Hom.: 2819 Cov.: 17 AF XY: 0.0618 AC XY: 39640 AN XY: 641386

African (AFR) AF: 0.0106 AC: 313 AN: 29498

American (AMR) AF: 0.0357 AC: 1534 AN: 42952

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 801 AN: 24544

East Asian (EAS) AF: 0.000130 AC: 5 AN: 38320

South Asian (SAS) AF: 0.0237 AC: 1916 AN: 80720

European-Finnish (FIN) AF: 0.0701 AC: 3684 AN: 52564

Middle Eastern (MID) AF: 0.0511 AC: 274 AN: 5362

European-Non Finnish (NFE) AF: 0.0723 AC: 68398 AN: 945538

Other (OTH) AF: 0.0558 AC: 3012 AN: 53932

GnomAD4 genome AF: 0.0482 AC: 7339 AN: 152196 Hom.: 259 Cov.: 32 AF XY: 0.0470 AC XY: 3498 AN XY: 74396

African (AFR) AF: 0.0129 AC: 537 AN: 41550

American (AMR) AF: 0.0498 AC: 761 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4822

European-Finnish (FIN) AF: 0.0753 AC: 797 AN: 10578

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0712 AC: 4844 AN: 67992

Other (OTH) AF: 0.0595 AC: 126 AN: 2116

Alfa AF: 0.0445 Hom.: 103

Bravo AF: 0.0451

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.89
DANN	Benign	0.70
PhyloP100		-0.72
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: rs1397266; hg19: chr18-48452307;