5-71602621-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_022132.5(MCCC2):c.499T>C(p.Cys167Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MCCC2
NM_022132.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.99

Publications

3 publications found

Variant links:

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

MCCC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_022132.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 5-71602621-T-C is Pathogenic according to our data. Variant chr5-71602621-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCCC2	NM_022132.5 link	c.499T>C	p.Cys167Arg	missense_variant	Exon 5 of 17	ENST00000340941.11	NP_071415.1	Q9HCC0-1A0A140VK29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC2	ENST00000340941.11 link	c.499T>C	p.Cys167Arg	missense_variant	Exon 5 of 17	1	NM_022132.5	ENSP00000343657.6		Q9HCC0-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251476

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00000137

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.0000655

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000939

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 2 deficiency

Pathogenic:5

Feb 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 27, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 167 of the MCCC2 protein (p.Cys167Arg). This variant is present in population databases (rs119103222, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 11170888, 14680978). ClinVar contains an entry for this variant (Variation ID: 1923). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MCCC2 protein function. Experimental studies have shown that this missense change affects MCCC2 function (PMID: 14680978). For these reasons, this variant has been classified as Pathogenic. -

Dec 24, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Methylcrotonyl-CoA carboxylase deficiency

Pathogenic:1

May 31, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MCCC2 c.499T>C (p.Cys167Arg) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251476 control chromosomes. c.499T>C has been reported in the literature in at least one homozygous individual affected with Methylcrotonyl-CoA Carboxylase Deficiency (Desviat_2003, Gallardo_2001). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in almost complete loss of MCC activity in MCCB-deficient fibroblasts (0.3% of normal activity) (Desviat_2003). The following publications have been ascertained in the context of this evaluation (PMID: 14680978, 11170888). ClinVar contains an entry for this variant (Variation ID: 1923). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

.;H;.

PhyloP100

8.0

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-11

.;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.96

MutPred

0.95

Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);Gain of MoRF binding (P = 0.0175);

MVP

0.97

MPC

0.70

ClinPred

1.0

GERP RS

5.5

Varity_R

0.99

gMVP

0.99

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over