2-71110073-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032601.4(MCEE):c.428G>A(p.Arg143His) variant causes a missense change. The variant allele was found at a frequency of 0.00845 in 1,613,128 control chromosomes in the GnomAD database, including 395 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.024 ( 112 hom., cov: 31)

Exomes 𝑓: 0.0069 ( 283 hom. )

Consequence

MCEE
NM_032601.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.14

Publications

13 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P

MCEE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035372078).

BP6

Variant 2-71110073-C-T is Benign according to our data. Variant chr2-71110073-C-T is described in ClinVar as Benign. ClinVar VariationId is 336936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCEE	NM_032601.4 link	c.428G>A	p.Arg143His	missense_variant	Exon 3 of 3	ENST00000244217.6	NP_115990.3	Q96PE7
MCEE	XM_005264613.3 link	c.266G>A	p.Arg89His	missense_variant	Exon 3 of 3		XP_005264670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MCEE	ENST00000244217.6 link	c.428G>A	p.Arg143His	missense_variant	Exon 3 of 3	1	NM_032601.4	ENSP00000244217.5	Q96PE7
MCEE	ENST00000413592.5 link	c.134G>A	p.Arg45His	missense_variant	Exon 2 of 2	2		ENSP00000391140.1	H7BZS7
MCEE	ENST00000462609.2 link	n.374G>A		non_coding_transcript_exon_variant	Exon 5 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.0235

AC:

3578

AN:

152064

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0643

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0374

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00980

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00265

Gnomad OTH

AF:

0.0226

GnomAD2 exomes

AF:

0.0189

AC:

4749

AN:

251110

AF XY:

0.0155

show subpopulations

Gnomad AFR exome

AF:

0.0662

Gnomad AMR exome

AF:

0.0813

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00799

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00227

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.00688

AC:

10050

AN:

1460946

Hom.:

283

Cov.:

AF XY:

0.00654

AC XY:

4750

AN XY:

726816

show subpopulations

African (AFR)

AF:

0.0661

AC:

2212

AN:

33446

American (AMR)

AF:

0.0734

AC:

3282

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00126

AC:

AN:

26124

East Asian (EAS)

AF:

0.00580

AC:

230

AN:

39660

South Asian (SAS)

AF:

0.0125

AC:

1076

AN:

86220

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00222

AC:

2469

AN:

1111306

Other (OTH)

AF:

0.0110

AC:

664

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

520

1040

1560

2080

2600

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

384

576

768

960

<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:

0.0235

AC:

3583

AN:

152182

Hom.:

112

Cov.:

AF XY:

0.0219

AC XY:

1627

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0642

AC:

2666

AN:

41522

American (AMR)

AF:

0.0375

AC:

573

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3466

East Asian (EAS)

AF:

0.00983

AC:

AN:

5190

South Asian (SAS)

AF:

0.0122

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00265

AC:

180

AN:

67986

Other (OTH)

AF:

0.0223

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

183

366

549

732

915

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.00892

Hom.:

113

Bravo

AF:

0.0307

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.0583

AC:

257

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.0178

AC:

2157

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.00393

EpiControl

AF:

0.00290

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 25, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.0035

T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Pathogenic

3.3

.;M

PhyloP100

5.1

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

.;D

Vest4

0.18

MPC

0.58

ClinPred

0.067

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.85

Mutation Taster

=66/34

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