rs202247821

Positions:

• chr3-136329943-G-GCCC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_000532.5(PCCB):​c.1538_1540dup​(p.Ala513_Arg514insPro) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A513A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCCB NM_000532.5 inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.71

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000532.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000532.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-136329943-G-GCCC is Pathogenic according to our data. Variant chr3-136329943-G-GCCC is described in ClinVar as [Pathogenic]. Clinvar id is 12017.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCB	NM_000532.5	c.1538_1540dup	p.Ala513_Arg514insPro	inframe_insertion	15/15	ENST00000251654.9
PCCB	NM_001178014.2	c.1598_1600dup	p.Ala533_Arg534insPro	inframe_insertion	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCB	ENST00000251654.9	c.1538_1540dup	p.Ala513_Arg514insPro	inframe_insertion	15/15	1	NM_000532.5	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Propionic acidemia Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2000	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs202247821; hg19: chr3-136048785;