Genetic Variant NM_000532.5:c.2T>C (chr3-136250377-T-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_000532.5(PCCB):c.2T>C(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 Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 84 codons. Genomic position: 136255922. Lost 0.154 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-136250377-T-C is Pathogenic according to our data. Variant chr3-136250377-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1067629.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCB	NM_000532.5 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 15	ENST00000251654.9	NP_000523.2	P05166-1
PCCB	NM_001178014.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 16		NP_001171485.1	P05166-2
PCCB	XM_011512873.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 15	1	NM_000532.5	ENSP00000251654.4		P05166-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.28e-7

AC:

AN:

1374114

Hom.:

Cov.:

AF XY:

0.00000148

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

Sep 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. ClinVar contains an entry for this variant (Variation ID: 1067629). 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. For these reasons, this variant has been classified as Pathogenic. 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

0.64

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.34

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

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

PROVEAN

Benign

-0.81

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

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0040

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

Sift4G

Uncertain

0.0080

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

Polyphen

0.72

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

Vest4

0.59

MutPred

0.93

Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);

MVP

0.98

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.82

gMVP

0.76

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over