rs202247818

Variant names:

• chr3-136256586-G-A
• rs202247818
• NM_000532.5:c.335G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000532.5(PCCB):​c.335G>A​(p.Gly112Asp) variant causes a missense 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004293506: Studies have shown that this missense change alters PCCB gene expression (PMID:12757933).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G112S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.60
• Publications: 10 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 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004293506: Studies have shown that this missense change alters PCCB gene expression (PMID: 12757933).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-136256585-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1468741.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 61 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: -0.86701 (below the threshold of 3.09). Trascript score misZ: -0.97134 (below the threshold of 3.09). GenCC associations: The gene is linked to propionic acidemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 3-136256586-G-A is Pathogenic according to our data. Variant chr3-136256586-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38883.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.335G>A	p.Gly112Asp	missense	Exon 3 of 15	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.335G>A	p.Gly112Asp	missense	Exon 3 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.335G>A	p.Gly112Asp	missense	Exon 3 of 15	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.335G>A	p.Gly112Asp	missense	Exon 3 of 16	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.335G>A	p.Gly112Asp	missense	Exon 3 of 9	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Propionic acidemia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		9.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.94		Loss of methylation at R113 (P = 0.0278)
MVP		0.99
MPC		0.58
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.99
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs202247818; hg19: chr3-135975428; COSMIC: COSV107244566; COSMIC: COSV107244566;