rs12516456

Variant names:

• chr5-71626789-G-A
• rs12516456
• NM_022132.5:c.738+36G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-71626789-G-A
• chr5-71626789-G-C

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -0.729
• Publications: 11 publications found

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]

MCCC2 Gene-Disease associations (from GenCC):

• 3-methylcrotonyl-CoA carboxylase 2 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 3-methylcrotonyl-CoA carboxylase deficiency

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
MCCC2	NM_022132.5	c.738+36G>A		intron_variant	Intron 7 of 16	ENST00000340941.11	NP_071415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC2	ENST00000340941.11	c.738+36G>A		intron_variant	Intron 7 of 16	1	NM_022132.5	ENSP00000343657.6

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

GnomAD2 exomes AF: 0.841 AC: 209654 AN: 249194 AF XY: 0.841

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 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

African (AFR) AF: 0.706 AC: 22934 AN: 32492

American (AMR) AF: 0.903 AC: 40146 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.897 AC: 23154 AN: 25806

East Asian (EAS) AF: 0.872 AC: 34397 AN: 39434

South Asian (SAS) AF: 0.834 AC: 71000 AN: 85160

European-Finnish (FIN) AF: 0.827 AC: 44083 AN: 53310

Middle Eastern (MID) AF: 0.859 AC: 4881 AN: 5680

European-Non Finnish (NFE) AF: 0.835 AC: 891206 AN: 1066706

Other (OTH) AF: 0.838 AC: 49284 AN: 58834

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

African (AFR) AF: 0.716 AC: 29719 AN: 41518

American (AMR) AF: 0.871 AC: 13325 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.889 AC: 3086 AN: 3472

East Asian (EAS) AF: 0.871 AC: 4521 AN: 5188

South Asian (SAS) AF: 0.846 AC: 4084 AN: 4826

European-Finnish (FIN) AF: 0.818 AC: 8665 AN: 10592

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.834 AC: 56731 AN: 68010

Other (OTH) AF: 0.829 AC: 1747 AN: 2108

Alfa AF: 0.829 Hom.: 87483

Bravo AF: 0.808

Asia WGS AF: 0.832 AC: 2893 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

3-methylcrotonyl-CoA carboxylase 2 deficiency Benign:1

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.66
PhyloP100		-0.73
Mutation Taster		=100/0	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: rs12516456; hg19: chr5-70922616; COSMIC: COSV60152876;