rs142403318

Variant names:

• chr3-136328849-C-G
• rs142403318
• NM_000532.5:c.1490C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-136328849-C-G
• chr3-136328849-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000532.5(PCCB):​c.1490C>G​(p.Ala497Gly) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A497V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.79
• Publications: 12 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000532.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.902

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.1490C>G	p.Ala497Gly	missense	Exon 14 of 15	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.1550C>G	p.Ala517Gly	missense	Exon 15 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.1490C>G	p.Ala497Gly	missense	Exon 14 of 15	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.1490C>G	p.Ala497Gly	missense	Exon 14 of 16	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.885-5431C>G		intron	N/A	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		6.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.86
Sift	Benign	0.080	T
Sift4G	Uncertain	0.023	D
Polyphen		0.95	P
Vest4		0.70
MutPred		0.79		Loss of stability (P = 0.0075)
MVP		0.94
MPC		0.50
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.83
Mutation Taster		=9/91	disease causing

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: rs142403318; hg19: chr3-136047691;