18-50919433-T-C

Position:

• chr18-50919433-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ME2	NM_002396.5	c.735-1023T>C		intron_variant		ENST00000321341.11	NP_002387.1
ME2	NM_001168335.2	c.735-1023T>C		intron_variant			NP_001161807.1
ME2	NR_174094.1	n.938-1023T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11	c.735-1023T>C		intron_variant		1	NM_002396.5	ENSP00000321070	P1

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

Gnomad4 AFR AF: 0.786

Gnomad4 AMR AF: 0.750

Gnomad4 ASJ AF: 0.650

Gnomad4 EAS AF: 0.658

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.557

Gnomad4 NFE AF: 0.624

Gnomad4 OTH AF: 0.691

Alfa AF: 0.656 Hom.: 4125

Bravo AF: 0.697

Asia WGS AF: 0.704 AC: 2450 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.5
DANN	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs685533; hg19: chr18-48445803;