rs146573280

Variant names:

• chr2-71124482-G-C
• rs146573280
• NM_032601.4:c.102C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-71124482-G-C
• chr2-71124482-G-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 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
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -14 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 VariationId is 195391.
• BP7: Synonymous conserved (PhyloP=0.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00611 (931/152298) while in subpopulation AMR AF = 0.0081 (124/15300). AF 95% confidence interval is 0.00695. There are 6 homozygotes in GnomAd4. There are 510 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.102C>G	p.Pro34Pro	synonymous	Exon 2 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.102C>G	p.Pro34Pro	synonymous	Exon 2 of 3	ENSP00000244217.5	Q96PE7
	MCEE	ENST00000486135.1	TSL:3	c.-184C>G		5_prime_UTR	Exon 3 of 3	ENSP00000441569.1	F5GZ54
	MCEE	ENST00000494660.6	TSL:2	c.-184C>G		5_prime_UTR	Exon 2 of 2	ENSP00000437361.1	F5GZ54

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

GnomAD2 exomes AF: 0.00577 AC: 1448 AN: 250870 AF XY: 0.00569

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 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

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00626 AC: 280 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00158 AC: 136 AN: 86250

European-Finnish (FIN) AF: 0.0166 AC: 887 AN: 53376

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00739 AC: 8217 AN: 1112002

Other (OTH) AF: 0.00717 AC: 433 AN: 60394

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

African (AFR) AF: 0.00128 AC: 53 AN: 41568

American (AMR) AF: 0.00810 AC: 124 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.0237 AC: 251 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00717 AC: 488 AN: 68030

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.3
DANN	Benign	0.51
PhyloP100		0.47
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs146573280; hg19: chr2-71351612;