3-136250377-TG-AA

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate 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. It is difficult to determine the true allele frequency of this variant because it is of type MNV, 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)
• Consequence: PCCB NM_000532.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.89
• Publications: 0 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: Myriad Women’s Health, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

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

• PVS1: Start lost variant, next in-frame start position is after 31 pathogenic variants. Next in-frame start position is after 84 codons. Genomic position: 136255922. Lost 0.154 part of the original CDS.
• PS1: Another start lost variant in NM_000532.5 (PCCB) was described as [Likely_pathogenic] in ClinVar
• PP5: Variant 3-136250377-TG-AA is Pathogenic according to our data. Variant chr3-136250377-TG-AA is described in ClinVar as Pathogenic. ClinVar VariationId is 1968405.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.2_3delTGinsAA	p.Met1?	start_lost	N/A	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.2_3delTGinsAA	p.Met1?	start_lost	N/A	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.2_3delTGinsAA	p.Met1?	start_lost	N/A	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.2_3delTGinsAA	p.Met1?	start_lost	N/A	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.2_3delTGinsAA	p.Met1?	start_lost	N/A	ENSP00000420759.1	E7ENC1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Propionic acidemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9

Splicing

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

Other links and lift over

hg19: chr3-135969219;