dbSNP rs996480567: PCCB:c.373-1246G>A (chr3-136259233-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

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

Publications

2 publications found

Variant links:

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

PCCB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein
PCCB	NM_000532.5 link	c.373-1246G>A		intron_variant	Intron 3 of 14	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2 link	c.430G>A	p.Glu144Lys	missense_variant, splice_region_variant	Exon 4 of 16		NP_001171485.1
PCCB	XM_011512873.2 link	c.373-1246G>A		intron_variant	Intron 3 of 10		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 link	c.373-1246G>A		intron_variant	Intron 3 of 14	1	NM_000532.5	ENSP00000251654.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

45632

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.0000162

AC:

AN:

924134

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

458228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20166

American (AMR)

AF:

0.00

AC:

AN:

17814

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17360

East Asian (EAS)

AF:

0.0000361

AC:

AN:

27702

South Asian (SAS)

AF:

0.00

AC:

AN:

38196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4160

European-Non Finnish (NFE)

AF:

0.0000192

AC:

AN:

730262

Other (OTH)

AF:

0.00

AC:

AN:

40342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Propionic acidemia

Uncertain:1

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.17

CADD

Benign

0.72

(source)

DANN

Benign

0.10

Eigen

Benign

-0.77

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.34

M_CAP

Benign

0.0040

MetaRNN

Benign

0.29

MetaSVM

Uncertain

0.14

PhyloP100

-1.0

PROVEAN

Benign

0.21

REVEL

Uncertain

0.33

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.20

MutPred

0.52

Gain of ubiquitination at E144 (P = 0.0311);

MVP

0.61

MPC

0.11

ClinPred

0.070

GERP RS

-1.4

gMVP

0.66

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over