2-71110074-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032601.4(MCEE):c.427C>T(p.Arg143Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00545 in 1,613,082 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0053 ( 10 hom., cov: 31)

Exomes 𝑓: 0.0055 ( 45 hom. )

Consequence

MCEE
NM_032601.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5O:1

Conservation

PhyloP100: 4.93

Publications

21 publications found

Variant links:

Genes affected

MCEE (HGNC:16732): (methylmalonyl-CoA epimerase) The product of this gene catalyzes the interconversion of D- and L-methylmalonyl-CoA during the degradation of branched chain amino acids. odd chain-length fatty acids, and other metabolites. Mutations in this gene result in methylmalonyl-CoA epimerase deficiency, which is presented as mild to moderate methylmalonic aciduria. [provided by RefSeq, Jul 2008]

MCEE Gene-Disease associations (from GenCC):

methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P

MCEE 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=0.010361373).

BP6

Variant 2-71110074-G-A is Benign according to our data. Variant chr2-71110074-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203810.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00533 (810/152052) while in subpopulation NFE AF = 0.0064 (435/67962). AF 95% confidence interval is 0.0059. There are 10 homozygotes in GnomAd4. There are 483 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032601.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCEE	NM_032601.4	MANE Select	c.427C>T	p.Arg143Cys	missense	Exon 3 of 3	NP_115990.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCEE	ENST00000244217.6	TSL:1 MANE Select	c.427C>T	p.Arg143Cys	missense	Exon 3 of 3	ENSP00000244217.5	Q96PE7
MCEE	ENST00000413592.5	TSL:2	c.133C>T	p.Arg45Cys	missense	Exon 2 of 2	ENSP00000391140.1	H7BZS7
MCEE	ENST00000916433.1		c.85C>T	p.Arg29Cys	missense	Exon 2 of 2	ENSP00000586492.1

Frequencies

GnomAD3 genomes

AF:

0.00533

AC:

810

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000991

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0290

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00640

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00549

AC:

1378

AN:

251090

AF XY:

0.00547

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.000840

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0262

Gnomad NFE exome

AF:

0.00633

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00546

AC:

7980

AN:

1461030

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

3923

AN XY:

726844

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33456

American (AMR)

AF:

0.000872

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00145

AC:

AN:

26120

East Asian (EAS)

AF:

0.000126

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.0230

AC:

1228

AN:

53362

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00577

AC:

6417

AN:

1111378

Other (OTH)

AF:

0.00340

AC:

205

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

358

717

1075

1434

1792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

210

420

630

840

1050

<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:

0.00533

AC:

810

AN:

152052

Hom.:

Cov.:

AF XY:

0.00650

AC XY:

483

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.000988

AC:

AN:

41500

American (AMR)

AF:

0.00105

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0290

AC:

305

AN:

10534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00640

AC:

435

AN:

67962

Other (OTH)

AF:

0.00237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

106

141

176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00568

Hom.:

Bravo

AF:

0.00308

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00733

AC:

ExAC

AF:

0.00525

AC:

637

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00502

EpiControl

AF:

0.00462

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency (4)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

4.3

PhyloP100

4.9

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-7.6

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MVP

0.90

MPC

0.41

ClinPred

0.17

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.82

gMVP

0.92

Mutation Taster

=65/35

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over