2-71110073-C-T

Variant names:

• chr2-71110073-C-T
• rs115175255
• NM_032601.4:c.428G>A

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: 5.14
• Publications: 13 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: Benign. The variant received -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 VariationId is 336936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032601.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCEE	NM_032601.4	MANE Select	c.428G>A	p.Arg143His	missense	Exon 3 of 3	NP_115990.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCEE	ENST00000244217.6	TSL:1 MANE Select	c.428G>A	p.Arg143His	missense	Exon 3 of 3	ENSP00000244217.5
	MCEE	ENST00000413592.5	TSL:2	c.134G>A	p.Arg45His	missense	Exon 2 of 2	ENSP00000391140.1
	MCEE	ENST00000916433.1		c.86G>A	p.Arg29His	missense	Exon 2 of 2	ENSP00000586492.1

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

GnomAD2 exomes AF: 0.0189 AC: 4749 AN: 251110 AF XY: 0.0155

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 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

African (AFR) AF: 0.0661 AC: 2212 AN: 33446

American (AMR) AF: 0.0734 AC: 3282 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26124

East Asian (EAS) AF: 0.00580 AC: 230 AN: 39660

South Asian (SAS) AF: 0.0125 AC: 1076 AN: 86220

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53370

Middle Eastern (MID) AF: 0.0141 AC: 81 AN: 5764

European-Non Finnish (NFE) AF: 0.00222 AC: 2469 AN: 1111306

Other (OTH) AF: 0.0110 AC: 664 AN: 60356

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

African (AFR) AF: 0.0642 AC: 2666 AN: 41522

American (AMR) AF: 0.0375 AC: 573 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00983 AC: 51 AN: 5190

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00265 AC: 180 AN: 67986

Other (OTH) AF: 0.0223 AC: 47 AN: 2106

Alfa AF: 0.00892 Hom.: 113

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0035	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.1
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	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
Mutation Taster		=66/34	polymorphism (auto)

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: rs115175255; hg19: chr2-71337203;