rs727504011

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_ModeratePM2PM5PP3_Moderate

The ENST00000340941.11(MCCC2):​c.1367C>T​(p.Ala456Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,528 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 Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A456P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MCCC2
ENST00000340941.11 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS1
Transcript ENST00000340941.11 (MCCC2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 451352
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr5-71649246-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2119835.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MCCC2NM_022132.5 linkuse as main transcriptc.1367C>T p.Ala456Val missense_variant 14/17 ENST00000340941.11 NP_071415.1
MCCC2NM_001363147.1 linkuse as main transcriptc.1253C>T p.Ala418Val missense_variant 13/16 NP_001350076.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MCCC2ENST00000340941.11 linkuse as main transcriptc.1367C>T p.Ala456Val missense_variant 14/171 NM_022132.5 ENSP00000343657 P1Q9HCC0-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152128
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251406
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461400
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727064
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152128
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74294
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 03, 2014- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.28
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D;.
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-3.6
D;D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
0.99
D;.
Vest4
0.72
MutPred
0.59
Loss of relative solvent accessibility (P = 0.0306);.;
MVP
0.98
MPC
0.48
ClinPred
0.99
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.90
gMVP
0.89

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727504011; hg19: chr5-70945074; COSMIC: COSV105902576; API