Genetic Variant ME2:c.1417+3480G>A (chr18-50935840-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.220

Publications

6 publications found

Variant links:

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)

ME2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ME2	NM_002396.5	MANE Select	c.1417+3480G>A	intron	N/A	NP_002387.1
ME2	NM_001168335.2		c.1417+3480G>A	intron	N/A	NP_001161807.1
ME2	NR_174094.1		n.1620+3480G>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ME2	ENST00000321341.11	TSL:1 MANE Select	c.1417+3480G>A	intron	N/A	ENSP00000321070.5
ME2	ENST00000382927.3	TSL:1	c.1417+3480G>A	intron	N/A	ENSP00000372384.2
ME2	ENST00000638937.1	TSL:5	c.1417+3480G>A	intron	N/A	ENSP00000492393.1

Frequencies

GnomAD3 genomes

AF:

0.680

AC:

101708

AN:

149596

Hom.:

34951

Cov.:

show subpopulations

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:

AN:

Hom.:

AF XY:

0.588

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.531

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.680

AC:

101799

AN:

149712

Hom.:

34987

Cov.:

AF XY:

0.681

AC XY:

49674

AN XY:

72910

show subpopulations

African (AFR)

AF:

0.777

AC:

31514

AN:

40570

American (AMR)

AF:

0.749

AC:

11189

AN:

14938

Ashkenazi Jewish (ASJ)

AF:

0.650

AC:

2255

AN:

3470

East Asian (EAS)

AF:

0.651

AC:

3314

AN:

5090

South Asian (SAS)

AF:

0.783

AC:

3748

AN:

4788

European-Finnish (FIN)

AF:

0.553

AC:

5429

AN:

9824

Middle Eastern (MID)

AF:

0.683

AC:

198

AN:

290

European-Non Finnish (NFE)

AF:

0.624

AC:

42308

AN:

67762

Other (OTH)

AF:

0.687

AC:

1427

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1580

3160

4739

6319

7899

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

804

1608

2412

3216

4020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.670

Hom.:

5007

Bravo

AF:

0.694

Asia WGS

AF:

0.701

AC:

2439

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

3.1

(source)

DANN

Benign

0.54

PhyloP100

-0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over