NM_000532.5:c.654+20T>C

Variant names:

• chr3-136283967-T-C
• rs3821445
• NM_000532.5:c.654+20T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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: Benign. The variant received -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 VariationId is 93231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

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.654+20T>C		intron	N/A	NP_000523.2
	PCCB	NM_001178014.2		c.714+20T>C		intron	N/A	NP_001171485.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCB	ENST00000251654.9	TSL:1 MANE Select	c.654+20T>C		intron	N/A	ENSP00000251654.4
	PCCB	ENST00000471595.5	TSL:1	c.654+20T>C		intron	N/A	ENSP00000417549.1
	PCCB	ENST00000478469.5	TSL:1	c.654+20T>C		intron	N/A	ENSP00000420759.1

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

GnomAD2 exomes AF: 0.160 AC: 40117 AN: 250622 AF XY: 0.163

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 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

African (AFR) AF: 0.100 AC: 3093 AN: 30836

American (AMR) AF: 0.152 AC: 6798 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 6570 AN: 25238

East Asian (EAS) AF: 0.0147 AC: 576 AN: 39060

South Asian (SAS) AF: 0.143 AC: 11922 AN: 83522

European-Finnish (FIN) AF: 0.120 AC: 6342 AN: 52704

Middle Eastern (MID) AF: 0.206 AC: 1041 AN: 5044

European-Non Finnish (NFE) AF: 0.202 AC: 199262 AN: 987054

Other (OTH) AF: 0.183 AC: 10179 AN: 55694

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

African (AFR) AF: 0.100 AC: 4157 AN: 41524

American (AMR) AF: 0.176 AC: 2693 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 895 AN: 3472

East Asian (EAS) AF: 0.00888 AC: 46 AN: 5178

South Asian (SAS) AF: 0.141 AC: 678 AN: 4818

European-Finnish (FIN) AF: 0.110 AC: 1167 AN: 10582

Middle Eastern (MID) AF: 0.223 AC: 65 AN: 292

European-Non Finnish (NFE) AF: 0.193 AC: 13137 AN: 68006

Other (OTH) AF: 0.185 AC: 391 AN: 2114

Alfa AF: 0.193 Hom.: 3830

Bravo AF: 0.159

Asia WGS AF: 0.0820 AC: 288 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Propionic acidemia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.3
DANN	Benign	0.58
PhyloP100		0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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