rs996480567

Positions:

• chr3-136259233-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000532.5(PCCB):​c.373-1246G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 924,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PCCB NM_000532.5 intron
• Scores: Splicing: ADA: 0.00003680
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.03

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28514868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCCB	NM_000532.5	c.373-1246G>A		intron_variant		ENST00000251654.9
PCCB	NM_001178014.2	c.430G>A	p.Glu144Lys	missense_variant, splice_region_variant	4/16
PCCB	XM_011512873.2	c.373-1246G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCB	ENST00000251654.9	c.373-1246G>A		intron_variant		1	NM_000532.5	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000162 AC: 15 AN: 924134 Hom.: 0 Cov.: 12 AF XY: 0.0000153 AC XY: 7 AN XY: 458228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000361

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Propionic acidemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	0.72
DANN	Benign	0.10
Eigen	Benign	-0.77
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PROVEAN	Benign	0.21	N
REVEL	Uncertain	0.33
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.20
MutPred		0.52		Gain of ubiquitination at E144 (P = 0.0311);
MVP		0.61
MPC		0.11
ClinPred		0.070	T
GERP RS		-1.4
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.010		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: rs996480567; hg19: chr3-135978075; COSMIC: COSV105091521; COSMIC: COSV105091521;