dbSNP rs202247821: PCCB:p.Ala513_Arg514insPro (chr3-136329943-G-GCCC) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_SupportingO9_Supporting

The NM_000532.5(PCCB):c.1538_1540dupCCC (p.Ala513_Arg514insPro) variant causes a disruptive inframe insertion change. The variant results in an in-frame change. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV006070938: At least one publication reports experimental evidence showing that this variant results in absent PCC activity in e. coli (Ravn_2000). PMID:10820128".

Frequency

Genomes: not found (cov: 32)

Consequence

PCCB
NM_000532.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 1.71

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

propionic acidemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, PanelApp Australia, Natera, G2P, Myriad Women's Health

PCCB links:

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new If you want to explore the variant's impact on the transcript NM_000532.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 points.

Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 3 pathogenic, 0 benign (OR vs. background: 35.0); Variant does not impact splicing — splice-hotspot path not applicable

In-frame indel in non-repetitive region, gene type unknown (O9 supporting); In-frame indel in non-repetitive region — gene: unknown gene type

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000532.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCB	NM_000532.5	MANE Select	c.1538_1540dupCCC	p.Ala513_Arg514insPro	disruptive_inframe_insertion	Exon 15 of 15	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.1598_1600dupCCC	p.Ala533_Arg534insPro	disruptive_inframe_insertion	Exon 16 of 16	NP_001171485.1	P05166-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCCB	ENST00000251654.9	TSL:1 MANE Select	c.1538_1540dupCCC	p.Ala513_Arg514insPro	disruptive_inframe_insertion	Exon 15 of 15	ENSP00000251654.4	P05166-1
PCCB	ENST00000471595.5	TSL:1	c.1538_1540dupCCC	p.Ala513_Arg514insPro	disruptive_inframe_insertion	Exon 15 of 16	ENSP00000417549.1	E9PDR0
PCCB	ENST00000478469.5	TSL:1	c.885-4336_885-4334dupCCC		intron	N/A	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Propionic acidemia (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.7

Mutation Taster

=62/38

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over