rs1789223

Positions:

• chr18-50935840-G-A
• chr18-50935840-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002396.5(ME2):​c.1417+3480G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 149,752 control chromosomes in the GnomAD database, including 34,993 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 (34987 hom., cov: 26)
  • Exomes 𝑓: 0.60 (6 hom.)
• Consequence: ME2 NM_002396.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.220

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=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.77 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ME2	NM_002396.5	c.1417+3480G>A		intron_variant		ENST00000321341.11
ME2	NM_001168335.2	c.1417+3480G>A		intron_variant
ME2	NR_174094.1	n.1620+3480G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ME2	ENST00000321341.11	c.1417+3480G>A		intron_variant		1	NM_002396.5	P1

Frequencies

GnomAD3 genomes AF: 0.680 AC: 101708 AN: 149596 Hom.: 34951 Cov.: 26

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.650

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.783

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.679

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.692

GnomAD4 exome AF: 0.600 AC: 24 AN: 40 Hom.: 6 AF XY: 0.588 AC XY: 20 AN XY: 34

Gnomad4 AFR exome AF: 1.00

Gnomad4 NFE exome AF: 0.531

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.680 AC: 101799 AN: 149712 Hom.: 34987 Cov.: 26 AF XY: 0.681 AC XY: 49674 AN XY: 72910

Gnomad4 AFR AF: 0.777

Gnomad4 AMR AF: 0.749

Gnomad4 ASJ AF: 0.650

Gnomad4 EAS AF: 0.651

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.553

Gnomad4 NFE AF: 0.624

Gnomad4 OTH AF: 0.687

Alfa AF: 0.666 Hom.: 4775

Bravo AF: 0.694

Asia WGS AF: 0.701 AC: 2439 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.1
DANN	Benign	0.54

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: rs1789223; hg19: chr18-48462210;