NM_022132.5:c.1015G>A

Variant names:

• chr5-71641018-G-A
• rs150591260
• NM_022132.5:c.1015G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 12P and 4B. PS3 PP5_Very_Strong BS2

The NM_022132.5(MCCC2):​c.1015G>A​(p.Val339Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,613,974 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000238962: Published functional studies demonstrated that V339M was associated with approximately 4% residual enzyme activity compared to wildtype (Baumgartner et al., 2001)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V339V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (4 hom.)
• Consequence: MCCC2 NM_022132.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28
• Conservation: PhyloP100: 9.28
• Publications: 24 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000238962: Published functional studies demonstrated that V339M was associated with approximately 4% residual enzyme activity compared to wildtype (Baumgartner et al., 2001);; SCV000575426: PS3:Supporting; SCV000644140: Experimental studies have shown that this missense change affects MCCC2 function (PMID: 11181649).; SCV000914262: expression studies in proband fibroblasts found the p.Val339Met variant resulted in 4-12% residual enzyme activity compared to wild type (Baumgartner et al. 2001; Wolfe et al. 2007).; SCV002318777: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 11181649)."; SCV005088761: Functional studies have shown that the variant is associated with approximately 4% residual enzyme activity compared to wildtype in vitro [PMID: 11181649, 17908719].; SCV003753862: "In vitro analysis of this mutation demonstrated reduced enzyme activity (4%) compared to wild type (Baumgartner, 2001)."; SCV004115138: This variant has been reported to greatly decrease the activity of the 3-methylcrotonyl-CoA carboxylase enzyme (Baumgartner et al. 2001. PubMed ID: 11181649).
• PP5: Variant 5-71641018-G-A is Pathogenic according to our data. Variant chr5-71641018-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 203805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.1015G>A	p.Val339Met	missense	Exon 11 of 17	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.901G>A	p.Val301Met	missense	Exon 10 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.1015G>A	p.Val339Met	missense	Exon 11 of 17	ENSP00000343657.6	Q9HCC0-1
	MCCC2	ENST00000629193.3	TSL:1	c.901G>A	p.Val301Met	missense	Exon 10 of 10	ENSP00000486535.2	A0A0D9SFE9
	MCCC2	ENST00000509358.7	TSL:1	c.*5G>A		3_prime_UTR	Exon 12 of 12	ENSP00000420994.3	D6RDF7

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000784 AC: 197 AN: 251374 AF XY: 0.000743

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000968

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.000676 AC: 988 AN: 1461688 Hom.: 4 Cov.: 30 AF XY: 0.000700 AC XY: 509 AN XY: 727154

African (AFR) AF: 0.000508 AC: 17 AN: 33478

American (AMR) AF: 0.00107 AC: 48 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 50 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5762

European-Non Finnish (NFE) AF: 0.000607 AC: 675 AN: 1111882

Other (OTH) AF: 0.00129 AC: 78 AN: 60388

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74462

African (AFR) AF: 0.000168 AC: 7 AN: 41562

American (AMR) AF: 0.00124 AC: 19 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000675 AC: 82

EpiCase AF: 0.00120

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	3-methylcrotonyl-CoA carboxylase 2 deficiency (17)
6	-	-	not provided (6)
2	-	-	Methylcrotonyl-CoA carboxylase deficiency (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	MCCC2-related disorder (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.99
MPC		0.50
ClinPred		0.27	T
GERP RS		5.7
Varity_R		0.84
gMVP		0.89
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.17		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: rs150591260; hg19: chr5-70936845; COSMIC: COSV108113409; COSMIC: COSV108113409;