3-136250377-TG-AA

Variant names:

• chr3-136250377-TG-AA
• NM_000532.5:c.2_3delTGinsAA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000532.5(PCCB):​c.2_3delTGinsAA​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCCB NM_000532.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.89

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 8 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 84 codons. Genomic position: 136255922. Lost 0.154 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-136250377-TG-AA is Pathogenic according to our data. Variant chr3-136250377-TG-AA is described in ClinVar as [Pathogenic]. Clinvar id is 1968405.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	c.2_3delTGinsAA	p.Met1?	start_lost		ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2	c.2_3delTGinsAA	p.Met1?	start_lost			NP_001171485.1
PCCB	XM_011512873.2	c.2_3delTGinsAA	p.Met1?	start_lost			XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9	c.2_3delTGinsAA	p.Met1?	start_lost		1	NM_000532.5	ENSP00000251654.4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Propionic acidemia Pathogenic:1

Sep 15, 2023

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PCCB protein in which other variant(s) (p.His59Gln) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1968405). This variant has not been reported in the literature in individuals affected with PCCB-related conditions. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-135969219;