rs1554138265

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_022132.5(MCCC2):c.1216+2T>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000684 in 1,461,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MCCC2
NM_022132.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.77

Publications

0 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 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-71646279-T-A is Pathogenic according to our data. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-71646279-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 982869.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.1216+2T>A		splice_donor_variant, intron_variant	Intron 13 of 16	ENST00000340941.11	NP_071415.1	Q9HCC0-1A0A140VK29
MCCC2	NM_001363147.1 link	c.1102+2T>A		splice_donor_variant, intron_variant	Intron 12 of 15		NP_001350076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCCC2	ENST00000340941.11 link	c.1216+2T>A		splice_donor_variant, intron_variant	Intron 13 of 16	1	NM_022132.5	ENSP00000343657.6		Q9HCC0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461194

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726948

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111564

Other (OTH)

AF:

0.00

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-methylcrotonyl-CoA carboxylase 2 deficiency

Pathogenic:3

Jun 02, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely 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

0.63

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

PhyloP100

6.8

GERP RS

5.3

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.98

Position offset: -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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over