chr3-136250380-C-T

Position:

chr3-136250380-C-T

Variant summary

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

The NM_000532.5(PCCB):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,526,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

PCCB
NM_000532.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.29

Variant links:

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]

PCCB links:

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ACMG classification

Classification made for transcript

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/exons	MANE	Protein
PCCB	NM_000532.5 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/16		NP_001171485.1
PCCB	XM_011512873.2 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/15	1	NM_000532.5	ENSP00000251654	P2	P05166-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000671

AC:

AN:

149054

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

80594

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000163

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

181

AN:

1374498

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

674544

show subpopulations

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:

0.0000266

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000163

Gnomad4 OTH exome

AF:

0.0000707

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000852

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Propionic acidemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 15, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the PCCB protein (p.Ala2Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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

0.24

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;.;T;T;T;.;.;.;.;T

Eigen

Benign

0.025

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

D;D;T;D;D;D;T;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.56

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

0.0

N;.;.;.;.;.;.;.;N;.;.

MutationTaster

Benign

0.61

N;N;N;N;N;N;N;N;N;N

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.46

N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.50

Sift

Benign

0.053

T;T;T;D;T;D;D;D;D;D;D

Sift4G

Uncertain

0.017

D;D;D;D;D;D;T;D;D;D;D

Polyphen

0.82

P;.;.;.;.;.;.;P;.;.;.

Vest4

0.51

MutPred

0.49

Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MVP

0.96

MPC

0.10

ClinPred

0.80

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Varity_R

0.17

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over