3-136250377-T-C

Variant names:

• chr3-136250377-T-C
• rs398123462
• NM_000532.5:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000532.5(PCCB):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,374,114 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: PCCB NM_000532.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.47
• 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 31 pathogenic variants. Next in-frame start position is after 84 codons. Genomic position: 136255922. Lost 0.154 part of the original CDS.
• PS1: Another start lost variant in NM_000532.5 (PCCB) was described as [Likely_pathogenic] in ClinVar as 93230
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-136250377-T-C is Pathogenic according to our data. Variant chr3-136250377-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 1067629.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCB	NM_000532.5	c.2T>C	p.Met1?	start_lost	Exon 1 of 15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 16		NP_001171485.1
PCCB	XM_011512873.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9	c.2T>C	p.Met1?	start_lost	Exon 1 of 15	1	NM_000532.5	ENSP00000251654.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1374114 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 674266

African (AFR) AF: 0.00 AC: 0 AN: 31108

American (AMR) AF: 0.00 AC: 0 AN: 34416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22432

East Asian (EAS) AF: 0.00 AC: 0 AN: 36556

South Asian (SAS) AF: 0.00 AC: 0 AN: 75010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5192

European-Non Finnish (NFE) AF: 9.39e-7 AC: 1 AN: 1064700

Other (OTH) AF: 0.00 AC: 0 AN: 56574

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Propionic acidemia Pathogenic:1

Sep 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PCCB-related conditions. ClinVar contains an entry for this variant (Variation ID: 1067629). This variant disrupts a region of the PCCB protein in which other variant(s) (p.His59Gln) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change affects the initiator methionine of the PCCB mRNA. The next in-frame methionine is located at codon 84. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.64
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.34	T;.;.;T;T;T;.;.;.;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		2.5
PROVEAN	Benign	-0.81	N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.72	P;.;.;.;.;.;.;P;.;.;.
Vest4		0.59
MutPred		0.93		Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);Gain of catalytic residue at M1 (P = 0.0262);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		-0.90	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.82
gMVP		0.76
Mutation Taster		=1/199	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: rs398123462; hg19: chr3-135969219;