rs202247821

Variant names:

• chr3-136329943-G-GCCC
• rs202247821
• NM_000532.5:c.1538_1540dupCCC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Moderate

The NM_000532.5(PCCB):​c.1538_1540dupCCC​(p.Ala513_Arg514insPro) variant causes a disruptive 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 (★). 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". Synonymous variant affecting the same amino acid position (i.e. R514R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCCB NM_000532.5 disruptive_inframe_insertion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.71
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine, Myriad Women's Health, ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: 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: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 VariationId is 12017.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

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

Sel.	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.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Propionic acidemia (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=62/38	disease causing (ClinVar)

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.

Other links and lift over

dbSNP: rs202247821;

hg19: chr3-136048785;