2-71124445-G-T

Variant names:

• chr2-71124445-G-T
• rs111033538
• NM_032601.4:c.139C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032601.4(MCEE):​c.139C>A​(p.Arg47Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MCEE NM_032601.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.53
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCEE	NM_032601.4	c.139C>A	p.Arg47Arg	synonymous_variant	Exon 2 of 3	ENST00000244217.6	NP_115990.3
MCEE	XM_047446039.1	c.139C>A	p.Arg47Arg	synonymous_variant	Exon 2 of 3		XP_047301995.1
MCEE	XM_005264613.3	c.139C>A	p.Arg47Arg	synonymous_variant	Exon 2 of 3		XP_005264670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCEE	ENST00000244217.6	c.139C>A	p.Arg47Arg	synonymous_variant	Exon 2 of 3	1	NM_032601.4	ENSP00000244217.5
MCEE	ENST00000413592.5	c.7C>A	p.Arg3Arg	synonymous_variant	Exon 1 of 2	2		ENSP00000391140.1
MCEE	ENST00000486135.1	c.-147C>A		5_prime_UTR_variant	Exon 3 of 3	3		ENSP00000441569.1
MCEE	ENST00000494660.6	c.-147C>A		5_prime_UTR_variant	Exon 2 of 2	2		ENSP00000437361.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727212

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.68
PhyloP100		4.5
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs111033538; hg19: chr2-71351575;