dbSNP rs794727960: PCCB:p.Val299Ile (chr3-136301040-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000532.5(PCCB):c.895G>A(p.Val299Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V299F) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PCCB
NM_000532.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.05

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a domain CoA carboxyltransferase C-terminal (size 239) in uniprot entity PCCB_HUMAN there are 29 pathogenic changes around while only 1 benign (97%) in NM_000532.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-136301040-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCB	NM_000532.5 link	c.895G>A	p.Val299Ile	missense_variant	Exon 9 of 15	ENST00000251654.9	NP_000523.2	P05166-1
PCCB	NM_001178014.2 link	c.955G>A	p.Val319Ile	missense_variant	Exon 10 of 16		NP_001171485.1	P05166-2
PCCB	XM_011512873.2 link	c.895G>A	p.Val299Ile	missense_variant	Exon 9 of 11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 link	c.895G>A	p.Val299Ile	missense_variant	Exon 9 of 15	1	NM_000532.5	ENSP00000251654.4		P05166-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.;.;D;D;D;.;.;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

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

M_CAP

Benign

0.081

MetaRNN

Uncertain

0.44

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.77

MutationAssessor

Benign

1.1

L;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.64

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

REVEL

Uncertain

0.39

Sift

Benign

0.096

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.34

T;T;T;T;T;T;T;T;T

Polyphen

0.097

B;.;.;.;.;.;.;B;.

Vest4

0.56

MutPred

0.42

Loss of helix (P = 0.1299);.;.;.;.;Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);.;

MVP

0.96

MPC

0.083

ClinPred

0.86

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.22

gMVP

0.53

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over