chr18-50947383-G-A

Variant names:

• chr18-50947383-G-A
• rs12277
• NM_002396.5:c.*199G>A

Variant summary

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

The NM_002396.5(ME2):​c.*199G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 559,414 control chromosomes in the GnomAD database, including 116,060 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 0.66 (33215 hom., cov: 32)
  • Exomes 𝑓: 0.63 (82845 hom.)
• Consequence: ME2 NM_002396.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.305
• Publications: 12 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.745 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.*199G>A		3_prime_UTR	Exon 16 of 16	NP_002387.1
	ME2	NR_174094.1		n.2086G>A		non_coding_transcript_exon	Exon 15 of 15
	ME2	NM_001168335.2		c.*344G>A		3_prime_UTR	Exon 14 of 14	NP_001161807.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ME2	ENST00000321341.11	TSL:1 MANE Select	c.*199G>A		3_prime_UTR	Exon 16 of 16	ENSP00000321070.5
	ME2	ENST00000382927.3	TSL:1	c.*344G>A		3_prime_UTR	Exon 14 of 14	ENSP00000372384.2
	ME2	ENST00000585680.2	TSL:5	n.*1405G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000491793.1

Frequencies

GnomAD3 genomes AF: 0.658 AC: 100004 AN: 151908 Hom.: 33185 Cov.: 32

Gnomad AFR AF: 0.728

Gnomad AMI AF: 0.460

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.673

GnomAD4 exome AF: 0.634 AC: 258469 AN: 407388 Hom.: 82845 Cov.: 4 AF XY: 0.641 AC XY: 136752 AN XY: 213372

African (AFR) AF: 0.737 AC: 8656 AN: 11752

American (AMR) AF: 0.743 AC: 11956 AN: 16086

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 8021 AN: 12770

East Asian (EAS) AF: 0.579 AC: 16713 AN: 28884

South Asian (SAS) AF: 0.769 AC: 28712 AN: 37358

European-Finnish (FIN) AF: 0.563 AC: 15110 AN: 26862

Middle Eastern (MID) AF: 0.694 AC: 1268 AN: 1828

European-Non Finnish (NFE) AF: 0.616 AC: 152696 AN: 247850

Other (OTH) AF: 0.639 AC: 15337 AN: 23998

GnomAD4 genome AF: 0.658 AC: 100093 AN: 152026 Hom.: 33215 Cov.: 32 AF XY: 0.660 AC XY: 49000 AN XY: 74274

African (AFR) AF: 0.728 AC: 30202 AN: 41484

American (AMR) AF: 0.732 AC: 11182 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2241 AN: 3464

East Asian (EAS) AF: 0.593 AC: 3066 AN: 5166

South Asian (SAS) AF: 0.766 AC: 3693 AN: 4822

European-Finnish (FIN) AF: 0.554 AC: 5846 AN: 10546

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.616 AC: 41842 AN: 67964

Other (OTH) AF: 0.669 AC: 1408 AN: 2106

Alfa AF: 0.637 Hom.: 40236

Bravo AF: 0.669

Asia WGS AF: 0.675 AC: 2347 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.14
DANN	Benign	0.76
PhyloP100		-0.30
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: rs12277; hg19: chr18-48473753;