5-71587479-C-G

Variant names:

• chr5-71587479-C-G
• rs747327321
• NM_022132.5:c.54C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_022132.5(MCCC2):​c.54C>G​(p.Ala18Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,384,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A18A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MCCC2 NM_022132.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.58
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 3-methylcrotonyl-CoA carboxylase deficiency

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 5-71587479-C-G is Benign according to our data. Variant chr5-71587479-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 513584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.58 with no splicing effect.

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.54C>G	p.Ala18Ala	synonymous	Exon 1 of 17	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.54C>G	p.Ala18Ala	synonymous	Exon 1 of 16	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.54C>G	p.Ala18Ala	synonymous	Exon 1 of 17	ENSP00000343657.6	Q9HCC0-1
	MCCC2	ENST00000509358.7	TSL:1	c.54C>G	p.Ala18Ala	synonymous	Exon 1 of 12	ENSP00000420994.3	D6RDF7
	MCCC2	ENST00000629193.3	TSL:1	c.54C>G	p.Ala18Ala	synonymous	Exon 1 of 10	ENSP00000486535.2	A0A0D9SFE9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000755 AC: 1 AN: 132490 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1384468 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 683190

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.0000841 AC: 3 AN: 35688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25118

East Asian (EAS) AF: 0.00 AC: 0 AN: 35816

South Asian (SAS) AF: 0.00 AC: 0 AN: 79146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078190

Other (OTH) AF: 0.00 AC: 0 AN: 57768

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	3-methylcrotonyl-CoA carboxylase 2 deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.7
DANN	Benign	0.77
PhyloP100		-3.6
PromoterAI		-0.077	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs747327321; hg19: chr5-70883306;