chr2-71124273-C-A

Position:

• chr2-71124273-C-A

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.311G>T​(p.Arg104Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,613,596 control chromosomes in the GnomAD database, including 25,168 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2680 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22488 hom.)
• Consequence: MCEE NM_032601.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.801

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=0.0028464198).
• BP6: Variant 2-71124273-C-A is Benign according to our data. Variant chr2-71124273-C-A is described in ClinVar as [Benign]. Clinvar id is 138183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCEE	NM_032601.4	c.311G>T	p.Arg104Leu	missense_variant	2/3	ENST00000244217.6	NP_115990.3
MCEE	XM_047446039.1	c.311G>T	p.Arg104Leu	missense_variant	2/3		XP_047301995.1
MCEE	XM_005264613.3	c.216+95G>T		intron_variant			XP_005264670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCEE	ENST00000244217.6	c.311G>T	p.Arg104Leu	missense_variant	2/3	1	NM_032601.4	ENSP00000244217	P1
MCEE	ENST00000486135.1	c.26G>T	p.Arg9Leu	missense_variant	3/3	3		ENSP00000441569
MCEE	ENST00000494660.6	c.26G>T	p.Arg9Leu	missense_variant	2/2	2		ENSP00000437361
MCEE	ENST00000413592.5	c.84+95G>T		intron_variant		2		ENSP00000391140

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27671 AN: 152066 Hom.: 2675 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.0917

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.191

GnomAD3 exomes AF: 0.171 AC: 43015 AN: 251120 Hom.: 3898 AF XY: 0.173 AC XY: 23463 AN XY: 135782

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.179

Gnomad SAS exome AF: 0.204

Gnomad FIN exome AF: 0.0954

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.172 AC: 252075 AN: 1461412 Hom.: 22488 Cov.: 33 AF XY: 0.173 AC XY: 125908 AN XY: 727016

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.177

Gnomad4 ASJ exome AF: 0.159

Gnomad4 EAS exome AF: 0.217

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.0994

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.182 AC: 27690 AN: 152184 Hom.: 2680 Cov.: 33 AF XY: 0.178 AC XY: 13259 AN XY: 74418

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.199

Gnomad4 SAS AF: 0.207

Gnomad4 FIN AF: 0.0917

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.195

Alfa AF: 0.168 Hom.: 3537

Bravo AF: 0.188

TwinsUK AF: 0.170 AC: 632

ALSPAC AF: 0.177 AC: 681

ESP6500AA AF: 0.228 AC: 1003

ESP6500EA AF: 0.168 AC: 1449

ExAC AF: 0.174 AC: 21100

EpiCase AF: 0.174

EpiControl AF: 0.177

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 17% of total chromosomes in ExAC -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.9
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.97	D;.;D
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N;.;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.5	D;N;N
REVEL	Benign	0.088
Sift	Uncertain	0.024	D;D;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.010	B;.;.
Vest4		0.038
MPC		0.13
ClinPred		0.0053	T
GERP RS		-4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6748672; hg19: chr2-71351403; COSMIC: COSV54905236;