3-136250391-C-G

Position:

• chr3-136250391-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000532.5(PCCB):​c.16C>G​(p.Arg6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.730

Genes affected

PCCB (HGNC:8654): (propionyl-CoA carboxylase subunit beta) The protein encoded by this gene is a subunit of the propionyl-CoA carboxylase (PCC) enzyme, which is involved in the catabolism of propionyl-CoA. PCC is a mitochondrial enzyme that probably acts as a dodecamer of six alpha subunits and six beta subunits. This gene encodes the beta subunit of PCC. Defects in this gene are a cause of propionic acidemia type II (PA-2). Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23658893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCB	NM_000532.5	c.16C>G	p.Arg6Gly	missense_variant	1/15	ENST00000251654.9
PCCB	NM_001178014.2	c.16C>G	p.Arg6Gly	missense_variant	1/16
PCCB	XM_011512873.2	c.16C>G	p.Arg6Gly	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCB	ENST00000251654.9	c.16C>G	p.Arg6Gly	missense_variant	1/15	1	NM_000532.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000643 AC: 1 AN: 155458 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 84774

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000156

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383414 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 680322

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.35e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Propionic acidemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 12, 2022

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 6 of the PCCB protein (p.Arg6Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PCCB-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCCB protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.39	T;.;.;T;T;T;.;.;.;.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.84	T;D;T;D;D;T;T;T;D;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.0	N;.;.;.;.;.;.;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.18	T;T;T;T;T;T;D;T;T;T;T
Polyphen		0.67	P;.;.;.;.;.;.;P;.;.;.
Vest4		0.31
MutPred		0.49		Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);
MVP		0.81
MPC		0.13
ClinPred		0.48	T
GERP RS		2.1
Varity_R		0.26
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs377681768; hg19: chr3-135969233;