rs61598773

Variant names:

• chr3-136283839-G-A
• rs61598773
• NM_000532.5:c.546G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The NM_000532.5(PCCB):​c.546G>A​(p.Arg182Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000935 in 1,608,040 control chromosomes in the GnomAD database, including 12 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (8 hom.)
• Consequence: PCCB NM_000532.5 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.94
• Publications: 3 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: Benign. The variant received -17 ACMG points.

• BP6: Variant 3-136283839-G-A is Benign according to our data. Variant chr3-136283839-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 383033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.94 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00492 (749/152278) while in subpopulation AFR AF = 0.0172 (715/41546). AF 95% confidence interval is 0.0162. There are 4 homozygotes in GnomAd4. There are 361 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.546G>A	p.Arg182Arg	splice_region synonymous	Exon 6 of 15	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.606G>A	p.Arg202Arg	splice_region synonymous	Exon 7 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.546G>A	p.Arg182Arg	splice_region synonymous	Exon 6 of 15	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.546G>A	p.Arg182Arg	splice_region synonymous	Exon 6 of 16	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.546G>A	p.Arg182Arg	splice_region synonymous	Exon 6 of 9	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes AF: 0.00494 AC: 751 AN: 152160 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00124 AC: 311 AN: 251410 AF XY: 0.000839

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.000781

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: 0.000326

GnomAD4 exome AF: 0.000518 AC: 754 AN: 1455762 Hom.: 8 Cov.: 29 AF XY: 0.000429 AC XY: 311 AN XY: 724820

African (AFR) AF: 0.0197 AC: 658 AN: 33346

American (AMR) AF: 0.000738 AC: 33 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5740

European-Non Finnish (NFE) AF: 0.00000813 AC: 9 AN: 1106540

Other (OTH) AF: 0.000848 AC: 51 AN: 60132

GnomAD4 genome AF: 0.00492 AC: 749 AN: 152278 Hom.: 4 Cov.: 32 AF XY: 0.00485 AC XY: 361 AN XY: 74470

African (AFR) AF: 0.0172 AC: 715 AN: 41546

American (AMR) AF: 0.00170 AC: 26 AN: 15288

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00196 Hom.: 8

Bravo AF: 0.00565

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.88
PhyloP100		1.9
Mutation Taster		=77/23	polymorphism

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: rs61598773; hg19: chr3-136002681;