rs199886085

Variant names:

• chr3-136283950-A-C
• rs199886085
• NM_000532.5:c.654+3A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_000532.5(PCCB):​c.654+3A>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000547 in 1,584,326 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (7 hom.)
• Consequence: PCCB NM_000532.5 splice_region, intron
• Scores: Splicing: ADA: 0.9938
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.68
• 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: Myriad Women’s Health, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 3-136283950-A-C is Benign according to our data. Variant chr3-136283950-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529438.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

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+3A>C		splice_region intron	N/A	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.714+3A>C		splice_region intron	N/A	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.654+3A>C		splice_region intron	N/A	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.654+3A>C		splice_region intron	N/A	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.654+3A>C		splice_region intron	N/A	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000999 AC: 251 AN: 251316 AF XY: 0.00128

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000564 AC: 808 AN: 1432020 Hom.: 7 Cov.: 25 AF XY: 0.000764 AC XY: 546 AN XY: 714354

African (AFR) AF: 0.0000304 AC: 1 AN: 32894

American (AMR) AF: 0.000224 AC: 10 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00646 AC: 554 AN: 85700

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53286

Middle Eastern (MID) AF: 0.00384 AC: 21 AN: 5474

European-Non Finnish (NFE) AF: 0.000169 AC: 183 AN: 1085070

Other (OTH) AF: 0.000623 AC: 37 AN: 59350

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00828 AC: 40 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68018

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000279 Hom.: 0

Bravo AF: 0.000185

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Propionic acidemia (3)
-	-	2	not provided (2)
-	-	1	PCCB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	35
DANN	Benign	0.95
PhyloP100		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.68		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199886085; hg19: chr3-136002792;