5-71587457-C-T

Variant names:

• chr5-71587457-C-T
• rs986973442
• NM_022132.5:c.32C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022132.5(MCCC2):​c.32C>T​(p.Pro11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,382,992 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000087 (0 hom.)
• Consequence: MCCC2 NM_022132.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.266
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09371787).

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.32C>T	p.Pro11Leu	missense	Exon 1 of 17	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.32C>T	p.Pro11Leu	missense	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.32C>T	p.Pro11Leu	missense	Exon 1 of 17	ENSP00000343657.6	Q9HCC0-1
	MCCC2	ENST00000509358.7	TSL:1	c.32C>T	p.Pro11Leu	missense	Exon 1 of 12	ENSP00000420994.3	D6RDF7
	MCCC2	ENST00000629193.3	TSL:1	c.32C>T	p.Pro11Leu	missense	Exon 1 of 10	ENSP00000486535.2	A0A0D9SFE9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000758 AC: 1 AN: 131870 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000204

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000868 AC: 12 AN: 1382992 Hom.: 0 Cov.: 32 AF XY: 0.0000103 AC XY: 7 AN XY: 682380

African (AFR) AF: 0.00 AC: 0 AN: 31534

American (AMR) AF: 0.00 AC: 0 AN: 35672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25102

East Asian (EAS) AF: 0.00 AC: 0 AN: 35762

South Asian (SAS) AF: 0.00 AC: 0 AN: 79084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4738

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1078082

Other (OTH) AF: 0.00 AC: 0 AN: 57716

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	7.6
DANN	Benign	0.89
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.094	T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.27
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.39	N
REVEL	Uncertain	0.36
Sift	Benign	0.071	T
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.34		Gain of helix (P = 0.0078)
MVP		0.37
MPC		0.10
ClinPred		0.091	T
GERP RS		-1.5
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.036
gMVP		0.39
Mutation Taster		=96/4	polymorphism

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: rs986973442; hg19: chr5-70883284;