NM_000532.5:c.967-46A>G

Variant names:

• chr3-136316895-A-G
• rs9833162
• NM_000532.5:c.967-46A>G

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.967-46A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 1,602,770 control chromosomes in the GnomAD database, including 92,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10861 hom., cov: 32)
  • Exomes 𝑓: 0.33 (81356 hom.)
• Consequence: PCCB NM_000532.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.882
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-136316895-A-G is Benign according to our data. Variant chr3-136316895-A-G is described in ClinVar as Benign. ClinVar VariationId is 256376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 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.967-46A>G		intron	N/A	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.1027-46A>G		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.967-46A>G		intron	N/A	ENSP00000251654.4	P05166-1
	PCCB	ENST00000471595.5	TSL:1	c.967-46A>G		intron	N/A	ENSP00000417549.1	E9PDR0
	PCCB	ENST00000478469.5	TSL:1	c.885-17385A>G		intron	N/A	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54738 AN: 151862 Hom.: 10847 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.00638

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.335

GnomAD2 exomes AF: 0.295 AC: 73976 AN: 250884 AF XY: 0.299

Gnomad AFR exome AF: 0.515

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.00327

Gnomad FIN exome AF: 0.302

Gnomad NFE exome AF: 0.340

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.327 AC: 473777 AN: 1450790 Hom.: 81356 Cov.: 30 AF XY: 0.328 AC XY: 236998 AN XY: 722492

African (AFR) AF: 0.512 AC: 17004 AN: 33238

American (AMR) AF: 0.165 AC: 7379 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8425 AN: 26062

East Asian (EAS) AF: 0.00202 AC: 80 AN: 39654

South Asian (SAS) AF: 0.338 AC: 29036 AN: 86008

European-Finnish (FIN) AF: 0.305 AC: 16292 AN: 53392

Middle Eastern (MID) AF: 0.343 AC: 1963 AN: 5728

European-Non Finnish (NFE) AF: 0.340 AC: 374275 AN: 1101968

Other (OTH) AF: 0.322 AC: 19323 AN: 60050

GnomAD4 genome AF: 0.360 AC: 54780 AN: 151980 Hom.: 10861 Cov.: 32 AF XY: 0.353 AC XY: 26187 AN XY: 74284

African (AFR) AF: 0.515 AC: 21306 AN: 41402

American (AMR) AF: 0.244 AC: 3723 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1113 AN: 3466

East Asian (EAS) AF: 0.00640 AC: 33 AN: 5158

South Asian (SAS) AF: 0.305 AC: 1471 AN: 4818

European-Finnish (FIN) AF: 0.300 AC: 3168 AN: 10556

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22939 AN: 67984

Other (OTH) AF: 0.331 AC: 700 AN: 2112

Alfa AF: 0.339 Hom.: 5220

Bravo AF: 0.360

Asia WGS AF: 0.154 AC: 536 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Propionic acidemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.39
PhyloP100		-0.88
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: rs9833162; hg19: chr3-136035737; COSMIC: COSV52445248;