5-71649162-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_022132.5(MCCC2):​c.1282G>C​(p.Ala428Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

MCCC2
NM_022132.5 missense

Scores

16
2
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.12
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a domain CoA carboxyltransferase C-terminal (size 246) in uniprot entity MCCB_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_022132.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MCCC2NM_022132.5 linkc.1282G>C p.Ala428Pro missense_variant 14/17 ENST00000340941.11 NP_071415.1 Q9HCC0-1A0A140VK29
MCCC2NM_001363147.1 linkc.1168G>C p.Ala390Pro missense_variant 13/16 NP_001350076.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MCCC2ENST00000340941.11 linkc.1282G>C p.Ala428Pro missense_variant 14/171 NM_022132.5 ENSP00000343657.6 Q9HCC0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D;.
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.7
H;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-4.9
D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.91
MutPred
0.92
Loss of stability (P = 0.1365);.;
MVP
1.0
MPC
0.59
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.99
gMVP
0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-70944989; API