rs12516456

chr5-71626789-G-Achr5-71626789-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022132.5(MCCC2):c.738+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.834 in 1,564,112 control chromosomes in the GnomAD database, including 544,577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49906 hom., cov: 32)
  • Exomes 𝑓: 0.84 (494671 hom.)
• Consequence: MCCC2 NM_022132.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.729

Genes affected

MCCC2 (HGNC:6937): (methylcrotonyl-CoA carboxylase subunit 2) This gene encodes the small subunit of 3-methylcrotonyl-CoA carboxylase. This enzyme functions as a heterodimer and catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA. Mutations in this gene are associated with 3-Methylcrotonylglycinuria, an autosomal recessive disorder of leucine catabolism. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2018]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-71626789-G-A is Benign according to our data. Variant chr5-71626789-G-A is described in ClinVar as [Benign]. Clinvar id is 261560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCCC2	NM_022132.5	c.738+36G>A		intron_variant		ENST00000340941.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCCC2	ENST00000340941.11	c.738+36G>A		intron_variant		1	NM_022132.5	P1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122752 AN: 152100 Hom.: 49870 Cov.: 32

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.871

Gnomad ASJ AF: 0.889

Gnomad EAS AF: 0.872

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.833

GnomAD3 exomes AF: 0.841 AC: 209654 AN: 249194 Hom.: 88400 AF XY: 0.841 AC XY: 113275 AN XY: 134746

Gnomad AFR exome AF: 0.710

Gnomad AMR exome AF: 0.906

Gnomad ASJ exome AF: 0.893

Gnomad EAS exome AF: 0.877

Gnomad SAS exome AF: 0.836

Gnomad FIN exome AF: 0.826

Gnomad NFE exome AF: 0.833

Gnomad OTH exome AF: 0.853

GnomAD4 exome AF: 0.837 AC: 1181085 AN: 1411894 Hom.: 494671 Cov.: 23 AF XY: 0.837 AC XY: 590273 AN XY: 705594

Gnomad4 AFR exome AF: 0.706

Gnomad4 AMR exome AF: 0.903

Gnomad4 ASJ exome AF: 0.897

Gnomad4 EAS exome AF: 0.872

Gnomad4 SAS exome AF: 0.834

Gnomad4 FIN exome AF: 0.827

Gnomad4 NFE exome AF: 0.835

Gnomad4 OTH exome AF: 0.838

GnomAD4 genome AF: 0.807 AC: 122847 AN: 152218 Hom.: 49906 Cov.: 32 AF XY: 0.810 AC XY: 60265 AN XY: 74426

Gnomad4 AFR AF: 0.716

Gnomad4 AMR AF: 0.871

Gnomad4 ASJ AF: 0.889

Gnomad4 EAS AF: 0.871

Gnomad4 SAS AF: 0.846

Gnomad4 FIN AF: 0.818

Gnomad4 NFE AF: 0.834

Gnomad4 OTH AF: 0.829

Alfa AF: 0.831 Hom.: 69053

Bravo AF: 0.808

Asia WGS AF: 0.832 AC: 2893 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

3-methylcrotonyl-CoA carboxylase 2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.1
Dann	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs12516456; hg19: chr5-70922616; COSMIC: COSV60152876;