rs1304714042

Variant names:

• chr3-136262016-G-A
• rs1304714042
• NM_000532.5:c.494G>A
• PCCB p.Arg165Gln

Your query was ambiguous. Multiple possible variants found:

• chr3-136262016-G-A
• chr3-136262016-G-C

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000532.5(PCCB):​c.494G>A​(p.Arg165Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000355 in 1,408,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000941854: Experimental studies have shown that this missense change affects PCCB function (PMID:12757933)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.50
• Publications: 7 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: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine, Myriad Women's Health, ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000941854: Experimental studies have shown that this missense change affects PCCB function (PMID: 12757933).; SCV003923312: Functional studies demonstrate that this variant has a damaging effect on the gene or gene product (Pérez-Cerdá C et al., 2003).; SCV005381141: The variant results in <1% of wild type PCC activity (Perez-Cerda_2003). PMID: 11749052, 12559849
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000532.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-136262016-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2677518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.971
• PP5: Variant 3-136262016-G-A is Pathogenic according to our data. Variant chr3-136262016-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 551146.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.494G>A	p.Arg165Gln	missense	Exon 5 of 15	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.554G>A	p.Arg185Gln	missense	Exon 6 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.494G>A	p.Arg165Gln	missense	Exon 5 of 15	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.494G>A	p.Arg165Gln	missense	Exon 5 of 16	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.494G>A	p.Arg165Gln	missense	Exon 5 of 9	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000589 AC: 1 AN: 169706 AF XY: 0.0000112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000355 AC: 5 AN: 1408544 Hom.: 0 Cov.: 30 AF XY: 0.00000288 AC XY: 2 AN XY: 695426

African (AFR) AF: 0.00 AC: 0 AN: 32492

American (AMR) AF: 0.00 AC: 0 AN: 36374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25214

East Asian (EAS) AF: 0.00 AC: 0 AN: 37268

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79928

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000277 AC: 3 AN: 1083242

Other (OTH) AF: 0.0000171 AC: 1 AN: 58404

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Propionic acidemia (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		9.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.86
Mutation Taster		=0/100	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1304714042;

hg19: chr3-135980858;