chr2-71124482-G-C

Position:

• chr2-71124482-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_032601.4(MCEE):​c.102C>G​(p.Pro34Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 1,614,128 control chromosomes in the GnomAD database, including 56 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 0.0061 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (50 hom.)
• Consequence: MCEE NM_032601.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.470

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-71124482-G-C is Benign according to our data. Variant chr2-71124482-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195391.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=4}.
• BP7: Synonymous conserved (PhyloP=0.47 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCEE	NM_032601.4	c.102C>G	p.Pro34Pro	synonymous_variant	2/3	ENST00000244217.6	NP_115990.3
MCEE	XM_047446039.1	c.102C>G	p.Pro34Pro	synonymous_variant	2/3		XP_047301995.1
MCEE	XM_005264613.3	c.102C>G	p.Pro34Pro	synonymous_variant	2/3		XP_005264670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCEE	ENST00000244217.6	c.102C>G	p.Pro34Pro	synonymous_variant	2/3	1	NM_032601.4	ENSP00000244217.5
MCEE	ENST00000486135.1	c.-184C>G		5_prime_UTR_variant	3/3	3		ENSP00000441569.1
MCEE	ENST00000494660.6	c.-184C>G		5_prime_UTR_variant	2/2	2		ENSP00000437361.1
MCEE	ENST00000413592.5	c.-31C>G		upstream_gene_variant		2		ENSP00000391140.1

Frequencies

GnomAD3 genomes AF: 0.00612 AC: 932 AN: 152180 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00719

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00577 AC: 1448 AN: 250870 Hom.: 9 AF XY: 0.00569 AC XY: 772 AN XY: 135716

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00576

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00686 AC: 10022 AN: 1461830 Hom.: 50 Cov.: 34 AF XY: 0.00678 AC XY: 4932 AN XY: 727210

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00626

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00158

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.00739

Gnomad4 OTH exome AF: 0.00717

GnomAD4 genome AF: 0.00611 AC: 931 AN: 152298 Hom.: 6 Cov.: 33 AF XY: 0.00685 AC XY: 510 AN XY: 74462

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00810

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0237

Gnomad4 NFE AF: 0.00717

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00537 Hom.: 1

Bravo AF: 0.00504

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00638

EpiControl AF: 0.00605

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency Uncertain:1 Benign:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2016	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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

MCEE: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.3
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs146573280; hg19: chr2-71351612;