rs727504010

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_022132.5(MCCC2):c.994C>T(p.Arg332*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,613,586 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

MCCC2
NM_022132.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.81

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.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-71635241-C-T is Pathogenic according to our data. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71635241-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 167279.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.994C>T	p.Arg332*	stop_gained	Exon 10 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.994C>T	p.Arg332*	stop_gained	Exon 10 of 17	1	NM_022132.5	ENSP00000343657.6		Q9HCC0-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000517

AC:

AN:

251452

AF XY:

0.0000736

show subpopulations

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461514

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.000278

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1111708

Other (OTH)

AF:

0.0000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.00000658

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000465

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 2 deficiency

Pathogenic:6

May 13, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dysmorphism: Short stature, triangular facies, blue sclera, hypospadias, ambiguous genitalia Clinical suspicion: Noonan syndrome/Atypical RS Genes of interest: DPH1/TMEM94 -

Jun 20, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg332*) in the MCCC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MCCC2 are known to be pathogenic (PMID: 11181649, 22642865). This variant is present in population databases (rs727504010, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with 3MCC deficiency (PMID: 16010683). ClinVar contains an entry for this variant (Variation ID: 167279). For these reasons, this variant has been classified as Pathogenic. -

Mar 26, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jan 21, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.89

PhyloP100

2.8

Vest4

0.38

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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