rs649224

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_002396.5(ME2):c.1349G>A(p.Gly450Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.09 in 1,611,000 control chromosomes in the GnomAD database, including 8,917 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.14 ( 2305 hom., cov: 32)

Exomes 𝑓: 0.085 ( 6612 hom. )

Consequence

ME2
NM_002396.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.287

Publications

29 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028408766).

BP6

Variant 18-50932292-G-A is Benign according to our data. Variant chr18-50932292-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060471.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ME2	NM_002396.5 link	c.1349G>A	p.Gly450Glu	missense_variant	Exon 13 of 16	ENST00000321341.11	NP_002387.1	P23368-1
ME2	NM_001168335.2 link	c.1349G>A	p.Gly450Glu	missense_variant	Exon 13 of 14		NP_001161807.1	P23368-2
ME2	NR_174094.1 link	n.1552G>A		non_coding_transcript_exon_variant	Exon 13 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ME2	ENST00000321341.11 link	c.1349G>A	p.Gly450Glu	missense_variant	Exon 13 of 16	1	NM_002396.5	ENSP00000321070.5		P23368-1

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21456

AN:

151886

Hom.:

2296

Cov.:

show subpopulations

Gnomad AFR

AF:

0.302

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.0998

Gnomad ASJ

AF:

0.145

Gnomad EAS

AF:

0.0986

Gnomad SAS

AF:

0.0937

Gnomad FIN

AF:

0.0587

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.0734

Gnomad OTH

AF:

0.140

GnomAD2 exomes

AF:

0.0924

AC:

23139

AN:

250408

AF XY:

0.0904

show subpopulations

Gnomad AFR exome

AF:

0.306

Gnomad AMR exome

AF:

0.0630

Gnomad ASJ exome

AF:

0.128

Gnomad EAS exome

AF:

0.0881

Gnomad FIN exome

AF:

0.0568

Gnomad NFE exome

AF:

0.0738

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.0846

AC:

123447

AN:

1458996

Hom.:

6612

Cov.:

AF XY:

0.0848

AC XY:

61533

AN XY:

725864

show subpopulations

African (AFR)

AF:

0.325

AC:

10823

AN:

33344

American (AMR)

AF:

0.0677

AC:

3017

AN:

44554

Ashkenazi Jewish (ASJ)

AF:

0.131

AC:

3425

AN:

26074

East Asian (EAS)

AF:

0.124

AC:

4896

AN:

39568

South Asian (SAS)

AF:

0.0947

AC:

8132

AN:

85910

European-Finnish (FIN)

AF:

0.0583

AC:

3111

AN:

53358

Middle Eastern (MID)

AF:

0.154

AC:

883

AN:

5752

European-Non Finnish (NFE)

AF:

0.0747

AC:

82948

AN:

1110180

Other (OTH)

AF:

0.103

AC:

6212

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

5309

10618

15928

21237

26546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3314

6628

9942

13256

16570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.141

AC:

21505

AN:

152004

Hom.:

2305

Cov.:

AF XY:

0.140

AC XY:

10421

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.302

AC:

12510

AN:

41394

American (AMR)

AF:

0.0996

AC:

1521

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.145

AC:

505

AN:

3472

East Asian (EAS)

AF:

0.0988

AC:

510

AN:

5160

South Asian (SAS)

AF:

0.0942

AC:

454

AN:

4818

European-Finnish (FIN)

AF:

0.0587

AC:

621

AN:

10580

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0734

AC:

4990

AN:

67994

Other (OTH)

AF:

0.139

AC:

294

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

892

1783

2675

3566

4458

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

224

448

672

896

1120

<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:

0.114

Hom.:

1037

Bravo

AF:

0.151

TwinsUK

AF:

0.0868

AC:

322

ALSPAC

AF:

0.0727

AC:

280

ESP6500AA

AF:

0.285

AC:

1257

ESP6500EA

AF:

0.0769

AC:

661

ExAC

AF:

0.0970

AC:

11783

Asia WGS

AF:

0.0970

AC:

340

AN:

3474

EpiCase

AF:

0.0802

EpiControl

AF:

0.0812

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ME2-related disorder

Benign:1

Nov 15, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.67

CADD

Benign

9.9

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.017

T;.;.;.;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.81

T;T;T;T;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.74

N;.;N;.;.;.;.

PhyloP100

0.29

PrimateAI

Benign

0.30

PROVEAN

Benign

0.46

N;.;N;.;.;.;.

REVEL

Benign

0.039

Sift

Benign

0.42

T;.;T;.;.;.;.

Sift4G

Benign

0.56

T;.;T;.;.;.;.

Polyphen

0.0

B;.;.;.;.;.;.

Vest4

0.037

MPC

0.39

ClinPred

0.00073

GERP RS

-4.5

Varity_R

0.066

gMVP

0.75

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over