NM_000532.5:c.-8_12delCAGCAAAAATGGCGGCGGCA

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePP5_Moderate

The NM_000532.5(PCCB):c.-8_12delCAGCAAAAATGGCGGCGGCA(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,357,372 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

PCCB
NM_000532.5 frameshift, start_lost

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.391

Publications

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

PCCB links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 215 pathogenic variants in the truncated region.

PS1

Another start lost variant in NM_000532.5 (PCCB) was described as [Likely_pathogenic] in ClinVar as 93230

PP5

Variant 3-136250362-CCGGCACAGCAAAAATGGCGG-C is Pathogenic according to our data. Variant chr3-136250362-CCGGCACAGCAAAAATGGCGG-C is described in ClinVar as [Pathogenic]. Clinvar id is 1069994.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCB	NM_000532.5 link	c.-8_12delCAGCAAAAATGGCGGCGGCA	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 15	ENST00000251654.9	NP_000523.2	P05166-1
PCCB	NM_000532.5 link	c.-8_12delCAGCAAAAATGGCGGCGGCA		5_prime_UTR_variant	Exon 1 of 15	ENST00000251654.9	NP_000523.2	P05166-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 link	c.-8_12delCAGCAAAAATGGCGGCGGCA	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 15	1	NM_000532.5	ENSP00000251654.4		P05166-1
PCCB	ENST00000251654.9 link	c.-8_12delCAGCAAAAATGGCGGCGGCA		5_prime_UTR_variant	Exon 1 of 15	1	NM_000532.5	ENSP00000251654.4		P05166-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000147

AC:

AN:

1357372

Hom.:

AF XY:

0.00000301

AC XY:

AN XY:

663802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30838

American (AMR)

AF:

0.00

AC:

AN:

32592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21652

East Asian (EAS)

AF:

0.00

AC:

AN:

35988

South Asian (SAS)

AF:

0.00

AC:

AN:

71972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4902

European-Non Finnish (NFE)

AF:

0.00000189

AC:

AN:

1056270

Other (OTH)

AF:

0.00

AC:

AN:

55942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Propionic acidemia

Pathogenic:1

Nov 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the PCCB mRNA. The next in-frame methionine is located at codon 84. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with propionic acidemia (internal data). ClinVar contains an entry for this variant (Variation ID: 1069994). This variant disrupts the p.Arg44 amino acid residue in PCCB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9683601, 12007220, 12757933). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.39

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over