3-136250378-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000532.5(PCCB):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000393 in 1,527,438 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: PCCB NM_000532.5 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.89

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000532.5 (PCCB) was described as [Pathogenic] in ClinVar as 93228
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-136250378-G-A is Pathogenic according to our data. Variant chr3-136250378-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 93230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCB	NM_000532.5	c.3G>A	p.Met1?	start_lost	1/15	ENST00000251654.9
PCCB	NM_001178014.2	c.3G>A	p.Met1?	start_lost	1/16
PCCB	XM_011512873.2	c.3G>A	p.Met1?	start_lost	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCB	ENST00000251654.9	c.3G>A	p.Met1?	start_lost	1/15	1	NM_000532.5	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000364 AC: 5 AN: 1375194 Hom.: 0 Cov.: 31 AF XY: 0.00000296 AC XY: 2 AN XY: 674906

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: 0.00000469

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 14, 2012

- -

Propionic acidemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 23, 2022

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. ClinVar contains an entry for this variant (Variation ID: 93230). This variant has not been reported in the literature in individuals affected with PCCB-related conditions. 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 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	D
BayesDel_noAF	Pathogenic	0.67
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.33	T;.;.;T;T;T;.;.;.;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-0.76	N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.70
Sift	Benign	0.030	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.056	T;D;D;D;D;D;T;D;D;D;D
Polyphen		0.53	P;.;.;.;.;.;.;P;.;.;.
Vest4		0.77
MutPred		0.93		Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);
MVP		0.98
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.74
gMVP		0.70

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

Other links and lift over

dbSNP: rs398123464; hg19: chr3-135969220;