dbSNP rs202247821: PCCB:p.Ala513_Arg514insPro (chr3-136329943-G-GCCC) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM4_SupportingPP5_Moderate

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 ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 points.

PS3

Well-established functional study supports damaging effect (PS3); SCV006070938: At least one publication reports experimental evidence showing that this variant results in absent PCC activity in e. coli (Ravn_2000). PMID: 10820128

PM1

Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 3 pathogenic, 0 benign (OR vs. background: 35.0).

PM2

Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 moderate.

PM4

Single amino-acid in-frame indel in non-repetitive region — protein length change, supporting (PM4 +1); In-frame indel in non-repetitive region — protein length change (1 AA).

PP5

ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

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 ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over