rs119103225

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_022132.5(MCCC2):c.569A>C(p.His190Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H190Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MCCC2
NM_022132.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.99

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
3-methylcrotonyl-CoA carboxylase deficiency
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

MCCC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_022132.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-71604412-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198252.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

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.569A>C	p.His190Pro	missense	Exon 6 of 17	NP_071415.1	A0A140VK29
	MCCC2	NM_001363147.1		c.569A>C	p.His190Pro	missense	Exon 6 of 16	NP_001350076.1	Q9HCC0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCCC2	ENST00000340941.11	TSL:1 MANE Select	c.569A>C	p.His190Pro	missense	Exon 6 of 17	ENSP00000343657.6	Q9HCC0-1
MCCC2	ENST00000509358.7	TSL:1	c.569A>C	p.His190Pro	missense	Exon 6 of 12	ENSP00000420994.3	D6RDF7
MCCC2	ENST00000629193.3	TSL:1	c.569A>C	p.His190Pro	missense	Exon 6 of 10	ENSP00000486535.2	A0A0D9SFE9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

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:

8.99e-7

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

PhyloP100

9.0

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-9.5

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.94

MutPred

0.80

Loss of catalytic residue at R188 (P = 0.0666)

MVP

0.99

MPC

0.65

ClinPred

1.0

GERP RS

5.6

Varity_R

0.97

gMVP

0.96

Mutation Taster

=1/99

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over