2-71124406-T-G

Position:

chr2-71124406-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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 id is 203812.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, not_provided=1}. Variant chr2-71124406-T-G is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCEE	NM_032601.4 linkuse as main transcript	c.178A>C	p.Lys60Gln	missense_variant	2/3	ENST00000244217.6	NP_115990.3	Q96PE7
MCEE	XM_047446039.1 linkuse as main transcript	c.178A>C	p.Lys60Gln	missense_variant	2/3		XP_047301995.1
MCEE	XM_005264613.3 linkuse as main transcript	c.178A>C	p.Lys60Gln	missense_variant	2/3		XP_005264670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MCEE	ENST00000244217.6 linkuse as main transcript	c.178A>C	p.Lys60Gln	missense_variant	2/3	1	NM_032601.4	ENSP00000244217.5	Q96PE7
MCEE	ENST00000413592.5 linkuse as main transcript	c.46A>C	p.Lys16Gln	missense_variant	1/2	2		ENSP00000391140.1	H7BZS7
MCEE	ENST00000486135.1 linkuse as main transcript	c.-108A>C		5_prime_UTR_variant	3/3	3		ENSP00000441569.1	F5GZ54
MCEE	ENST00000494660.6 linkuse as main transcript	c.-108A>C		5_prime_UTR_variant	2/2	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

GnomAD3 exomes

AF:

0.00182

AC:

458

AN:

251370

Hom.:

AF XY:

0.00247

AC XY:

335

AN XY:

135884

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 SAS exome

AF:

0.0146

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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0136

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000993

GnomAD4 genome

AF:

0.000506

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0155

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000562

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

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	MCEE: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 06, 2018	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2017

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

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

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

Varity_R

0.51

gMVP

0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over