2-71110073-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.14

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 -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 id is 336936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71110073-C-T is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
MCEE	NM_032601.4	c.428G>A	p.Arg143His	missense_variant	3/3	ENST00000244217.6
MCEE	XM_005264613.3	c.266G>A	p.Arg89His	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCEE	ENST00000244217.6	c.428G>A	p.Arg143His	missense_variant	3/3	1	NM_032601.4	P1
MCEE	ENST00000413592.5	c.134G>A	p.Arg45His	missense_variant	2/2	2
MCEE	ENST00000462609.2	n.374G>A		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3578 AN: 152064 Hom.: 112 Cov.: 31

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

GnomAD3 exomes AF: 0.0189 AC: 4749 AN: 251110 Hom.: 183 AF XY: 0.0155 AC XY: 2107 AN XY: 135736

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 SAS exome AF: 0.0119

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.: 30 AF XY: 0.00654 AC XY: 4750 AN XY: 726816

Gnomad4 AFR exome AF: 0.0661

Gnomad4 AMR exome AF: 0.0734

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.00580

Gnomad4 SAS exome AF: 0.0125

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.0235 AC: 3583 AN: 152182 Hom.: 112 Cov.: 31 AF XY: 0.0219 AC XY: 1627 AN XY: 74408

Gnomad4 AFR AF: 0.0642

Gnomad4 AMR AF: 0.0375

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00983

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00265

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.00489 Hom.: 18

Bravo AF: 0.0307

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.0583 AC: 257

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.0178 AC: 2157

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00290

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.0035	T;T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.42	T
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	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.85

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: rs115175255; hg19: chr2-71337203;