rs147401037

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.178A>C(p.Lys60Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000821 in 1,614,158 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K60K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00085 ( 23 hom. )

Consequence

MCEE
NM_032601.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4O:1

Conservation

PhyloP100: 4.43

Publications

11 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009763122).

BP6

Variant 2-71124406-T-G is Benign according to our data. Variant chr2-71124406-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203812.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000506 (77/152272) while in subpopulation SAS AF = 0.0155 (75/4828). AF 95% confidence interval is 0.0127. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCEE	NM_032601.4 link	c.178A>C	p.Lys60Gln	missense_variant	Exon 2 of 3	ENST00000244217.6	NP_115990.3	Q96PE7
MCEE	XM_047446039.1 link	c.178A>C	p.Lys60Gln	missense_variant	Exon 2 of 3		XP_047301995.1
MCEE	XM_005264613.3 link	c.178A>C	p.Lys60Gln	missense_variant	Exon 2 of 3		XP_005264670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MCEE	ENST00000244217.6 link	c.178A>C	p.Lys60Gln	missense_variant	Exon 2 of 3	1	NM_032601.4	ENSP00000244217.5	Q96PE7
MCEE	ENST00000413592.5 link	c.46A>C	p.Lys16Gln	missense_variant	Exon 1 of 2	2		ENSP00000391140.1	H7BZS7
MCEE	ENST00000486135.1 link	c.-108A>C		5_prime_UTR_variant	Exon 3 of 3	3		ENSP00000441569.1	F5GZ54
MCEE	ENST00000494660.6 link	c.-108A>C		5_prime_UTR_variant	Exon 2 of 2	2		ENSP00000437361.1	F5GZ54

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0161

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00182

AC:

458

AN:

251370

AF XY:

0.00247

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000854

AC:

1249

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

895

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0136

AC:

1171

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112012

Other (OTH)

AF:

0.000993

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

173

259

346

432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000506

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41556

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.0155

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000300

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00213

AC:

259

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

Benign:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Lys60Gln variant in MCEE has been identified in an individual with methylmalonic aciduria (PMID: 17823972), but has also been identified in >1% of South Asian chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive methylmalonic aciduria. -

not provided

Benign:2

Feb 06, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.178A>C; p.Lys60Gln variant (rs147401037) was reported in the homozygous state in one patient with methylmalonic aciduria, ataxia, deteriorated motor function, dysarthria, and mild spastic paraparesis (Gradinger 2007). However, the patientâ€™s protein activity level was normal, as measured by incorporation of propionate into cellular macromolecules (Gradinger 2007). This variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 1.5% (identified on 454 out of 30,778 chromosomes, including 10 homozygotes), and is found in the 1000 Genomes Project BEB (Bengali from Bangladesh) population with a frequency of 5.2% (9 out of 172 chromosomes). The lysine at position 60 is highly conserved, considering 13 species, and computational analyses of the effects of the p.Lys60Gln variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available evidence, the p.Lys60Gln variant is likely to be benign. -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MCEE: BP4, BS1 -

not specified

Uncertain:1

Mar 08, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The K60Q variant in the MCEE gene has been reported previously as homozygous in a patient with methylmalonic aciduria (Gradinger et al., 2007). Gradinger et al. reported K60Q in a three year old patient with elevated methylmalonic acid excretion who presented with ataxia, deteriorated motor function, dysarthria, and mild spastic paraparesis. This variant is a non-conservative amino acid substitution of a positively charged Lysine with a neutral, polar Glutamine at a residue that is conserved in mammals. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. We interpret K60Q as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.37

T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D

MetaRNN

Benign

0.0098

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.5

.;L

PhyloP100

4.4

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.30

Sift

Benign

0.29

T;T

Sift4G

Benign

0.38

T;T

Polyphen

0.031

.;B

Vest4

0.77

MVP

0.77

MPC

0.13

ClinPred

0.042

GERP RS

2.8

PromoterAI

0.019

Neutral

(source)

Varity_R

0.51

gMVP

0.62

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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