3-136250389-T-G

Variant names:

• chr3-136250389-T-G
• rs1292452485
• NM_000532.5:c.14T>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000532.5(PCCB):​c.14T>G​(p.Leu5*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L5L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCCB NM_000532.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.00
• 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: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet, ClinGen, Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 208 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-136250389-T-G is Pathogenic according to our data. Variant chr3-136250389-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 556077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.14T>G	p.Leu5*	stop_gained	Exon 1 of 15	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.14T>G	p.Leu5*	stop_gained	Exon 1 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.14T>G	p.Leu5*	stop_gained	Exon 1 of 15	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.14T>G	p.Leu5*	stop_gained	Exon 1 of 16	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.14T>G	p.Leu5*	stop_gained	Exon 1 of 9	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	34
DANN	Benign	0.92
Eigen	Benign	-0.0072
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.33	N
PhyloP100		0.0
Vest4		0.53
GERP RS		2.6
PromoterAI		0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=36/164	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1292452485; hg19: chr3-135969231;