chr3-136283967-T-C

Position:

• chr3-136283967-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000532.5(PCCB):​c.654+20T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,475,928 control chromosomes in the GnomAD database, including 26,379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2076 hom., cov: 32)
  • Exomes 𝑓: 0.19 (24303 hom.)
• Consequence: PCCB NM_000532.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.471

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-136283967-T-C is Benign according to our data. Variant chr3-136283967-T-C is described in ClinVar as [Benign]. Clinvar id is 93231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-136283967-T-C is described in Lovd as [Pathogenic]. Variant chr3-136283967-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCB	NM_000532.5	c.654+20T>C		intron_variant		ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2	c.714+20T>C		intron_variant			NP_001171485.1
PCCB	XM_011512873.2	c.654+20T>C		intron_variant			XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9	c.654+20T>C		intron_variant		1	NM_000532.5	ENSP00000251654	P2

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23543 AN: 152072 Hom.: 2077 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.00886

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.160 AC: 40117 AN: 250622 Hom.: 3780 AF XY: 0.163 AC XY: 22114 AN XY: 135520

Gnomad AFR exome AF: 0.0986

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.264

Gnomad EAS exome AF: 0.00740

Gnomad SAS exome AF: 0.142

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.198

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.186 AC: 245783 AN: 1323738 Hom.: 24303 Cov.: 20 AF XY: 0.185 AC XY: 123148 AN XY: 666582

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.152

Gnomad4 ASJ exome AF: 0.260

Gnomad4 EAS exome AF: 0.0147

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.202

Gnomad4 OTH exome AF: 0.183

GnomAD4 genome AF: 0.155 AC: 23546 AN: 152190 Hom.: 2076 Cov.: 32 AF XY: 0.152 AC XY: 11296 AN XY: 74412

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.258

Gnomad4 EAS AF: 0.00888

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.185

Alfa AF: 0.198 Hom.: 3039

Bravo AF: 0.159

Asia WGS AF: 0.0820 AC: 288 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 04, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Propionic acidemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.3
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs3821445; hg19: chr3-136002809; COSMIC: COSV104381252; COSMIC: COSV104381252;