MCCC2 p.Ala456Ala

Variant names:

• chr5-71649245-A-A
• ENST00000340941.11:c.

Your query was ambiguous. Multiple possible variants found:

• chr5-71649246--
• chr5-71649248-A-T
• chr5-71649248-A-C
• chr5-71649248-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022132.5(MCCC2):​c. variant causes a intron change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCCC2 NM_022132.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.67
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 3-methylcrotonyl-CoA carboxylase deficiency

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022132.5. 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
	MCCC2	NM_022132.5	MANE Select	c.		intron	N/A	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.		intron	N/A	NP_001350076.1	Q9HCC0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCCC2	ENST00000340941.11	TSL:1 MANE Select	c.		exon_region	Exon 14 of 17	ENSP00000343657.6	Q9HCC0-1
	MCCC2	ENST00000682876.1		c.		exon_region	Exon 15 of 18	ENSP00000508389.1	A0A804HLJ9
	MCCC2	ENST00000888940.1		c.		exon_region	Exon 14 of 17	ENSP00000558999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-70945072;