3-136293864-G-A

Position:

• chr3-136293864-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000251654.9(PCCB):​c.763G>A​(p.Gly255Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G255G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCCB ENST00000251654.9 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.52

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 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in ENST00000251654.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 3-136293864-G-A is Pathogenic according to our data. Variant chr3-136293864-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557375.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCB	NM_000532.5	c.763G>A	p.Gly255Ser	missense_variant, splice_region_variant	7/15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2	c.823G>A	p.Gly275Ser	missense_variant, splice_region_variant	8/16		NP_001171485.1
PCCB	XM_011512873.2	c.763G>A	p.Gly255Ser	missense_variant, splice_region_variant	7/11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9	c.763G>A	p.Gly255Ser	missense_variant, splice_region_variant	7/15	1	NM_000532.5	ENSP00000251654	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1387228 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 694666

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Propionic acidemia Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 22, 2018	- -
Likely pathogenic, criteria provided, single submitter	in vitro;research	Laboratory of Inherited Metabolic Diseases, Research centre for medical genetics	Feb 17, 2021	PM1, PM2, PM5, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;D;D;D;.;.;.;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Benign	0.33	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.084	T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.;.;D;.;.
Vest4		0.96
MutPred		0.82		Gain of relative solvent accessibility (P = 0.0023);.;.;.;.;Gain of relative solvent accessibility (P = 0.0023);.;Gain of relative solvent accessibility (P = 0.0023);.;Gain of relative solvent accessibility (P = 0.0023);
MVP		0.97
MPC		0.50
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.64
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553778909; hg19: chr3-136012706;