rs138436961

Positions:

• chr2-71110074-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000244217.6(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 ENST00000244217.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5 O:1
• Conservation: PhyloP100: 4.93

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]

ACMG classification

Verdict is Benign. Variant got -9 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 id is 203810.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=1, Uncertain_significance=1, not_provided=1}. Variant chr2-71110074-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCEE	NM_032601.4	c.427C>T	p.Arg143Cys	missense_variant	3/3	ENST00000244217.6	NP_115990.3
MCEE	XM_005264613.3	c.265C>T	p.Arg89Cys	missense_variant	3/3		XP_005264670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCEE	ENST00000244217.6	c.427C>T	p.Arg143Cys	missense_variant	3/3	1	NM_032601.4	ENSP00000244217	P1
MCEE	ENST00000413592.5	c.133C>T	p.Arg45Cys	missense_variant	2/2	2		ENSP00000391140
MCEE	ENST00000462609.2	n.373C>T		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 810 AN: 151934 Hom.: 10 Cov.: 31

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

GnomAD3 exomes AF: 0.00549 AC: 1378 AN: 251090 Hom.: 18 AF XY: 0.00547 AC XY: 743 AN XY: 135724

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 SAS exome AF: 0.0000654

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.: 45 Cov.: 30 AF XY: 0.00540 AC XY: 3923 AN XY: 726844

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0230

Gnomad4 NFE exome AF: 0.00577

Gnomad4 OTH exome AF: 0.00340

GnomAD4 genome AF: 0.00533 AC: 810 AN: 152052 Hom.: 10 Cov.: 31 AF XY: 0.00650 AC XY: 483 AN XY: 74286

Gnomad4 AFR AF: 0.000988

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0290

Gnomad4 NFE AF: 0.00640

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00563 Hom.: 8

Bravo AF: 0.00308

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00525 AC: 637

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 19, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	MCEE: BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 01, 2022

Variant summary: MCEE c.427C>T (p.Arg143Cys) results in a non-conservative amino acid change located in the vicinal oxygen chelate (VOC) domain (IPR037523) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0058 in 282430 control chromosomes (gnomAD), predominantly at a frequency of 0.026 within the Finnish subpopulation in the gnomAD database, including 15 homozygotes. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 52 fold of the estimated maximal expected allele frequency for a pathogenic variant in MCEE causing Methylmalonic Acidemia phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. Six assessments for this variant have been submitted to ClinVar after 2014 with conflicting assessments (benign n=3, likely benign n=1, VUS n=1, pathogenic n=1). Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	4.3	.;H
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.86
MVP		0.90
MPC		0.41
ClinPred		0.17	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.82
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs138436961; hg19: chr2-71337204; COSMIC: COSV54905209;