chr3-136250380-C-A

Variant names:

• chr3-136250380-C-A
• NM_000532.5:c.5C>A

Variant summary

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

The NM_000532.5(PCCB):​c.5C>A​(p.Ala2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,374,504 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.29

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCB	NM_000532.5	c.5C>A	p.Ala2Glu	missense_variant	Exon 1 of 15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2	c.5C>A	p.Ala2Glu	missense_variant	Exon 1 of 16		NP_001171485.1
PCCB	XM_011512873.2	c.5C>A	p.Ala2Glu	missense_variant	Exon 1 of 11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9	c.5C>A	p.Ala2Glu	missense_variant	Exon 1 of 15	1	NM_000532.5	ENSP00000251654.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1374504 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 674546

Gnomad4 AFR exome AF: 0.0000321

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000133

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.39e-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

Jan 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2 of the PCCB protein (p.Ala2Glu). 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	0.23
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.35	T;.;.;T;T;T;.;.;.;.;T
Eigen	Benign	0.0030
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.0	N;.;.;.;.;.;.;.;N;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.84	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.043	D;D;T;D;T;D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.68	P;.;.;.;.;.;.;P;.;.;.
Vest4		0.55
MutPred		0.42		Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);Gain of solvent accessibility (P = 0.1185);
MVP		0.97
MPC		0.12
ClinPred		0.87	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.35
gMVP		0.83

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: chr3-135969222;