Variant 3-136250377-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000532.5(PCCB):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,374,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

PCCB
NM_000532.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.47

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-136250377-T-G is Pathogenic according to our data. Variant chr3-136250377-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2745320.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PCCB	NM_000532.5 linkuse as main transcript	c.2T>G	p.Met1?	start_lost	1/15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2 linkuse as main transcript	c.2T>G	p.Met1?	start_lost	1/16		NP_001171485.1
PCCB	XM_011512873.2 linkuse as main transcript	c.2T>G	p.Met1?	start_lost	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.2T>G	p.Met1?	start_lost	1/15	1	NM_000532.5	ENSP00000251654	P2	P05166-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.28e-7

AC:

AN:

1374114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

674266

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.39e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Propionic acidemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PCCB protein in which other variant(s) (p.His59Gln) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with PCCB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the PCCB mRNA. The next in-frame methionine is located at codon 84. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.30

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

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

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

PROVEAN

Benign

-0.38

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

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0030

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

Polyphen

0.86

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

Vest4

0.82

MutPred

0.91

Gain of methylation at M1 (P = 7e-04);Gain of methylation at M1 (P = 7e-04);Gain of methylation at M1 (P = 7e-04);Gain of methylation at M1 (P = 7e-04);Gain of methylation at M1 (P = 7e-04);Gain of methylation at M1 (P = 7e-04);Gain of methylation at M1 (P = 7e-04);Gain of methylation at M1 (P = 7e-04);Gain of methylation at M1 (P = 7e-04);Gain of methylation at M1 (P = 7e-04);Gain of methylation at M1 (P = 7e-04);

MVP

0.98

ClinPred

0.99

GERP RS

5.0

Varity_R

0.96

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over