rs201986472

Positions:

chr3-136260542-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000251654.9(PCCB):c.429+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,607,904 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00069 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00063 ( 2 hom. )

Consequence

PCCB
ENST00000251654.9 splice_region, intron

Scores

Splicing: ADA: 0.00005771

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.308

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 3-136260542-G-A is Benign according to our data. Variant chr3-136260542-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 343463.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
PCCB	NM_000532.5 linkuse as main transcript	c.429+7G>A	splice_region_variant, intron_variant	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2 linkuse as main transcript	c.489+7G>A	splice_region_variant, intron_variant		NP_001171485.1
PCCB	XM_011512873.2 linkuse as main transcript	c.429+7G>A	splice_region_variant, intron_variant		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 linkuse as main transcript	c.429+7G>A		splice_region_variant, intron_variant		1	NM_000532.5	ENSP00000251654	P2	P05166-1

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000599

AC:

150

AN:

250496

Hom.:

AF XY:

0.000576

AC XY:

AN XY:

135362

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000461

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.000631

AC:

919

AN:

1455680

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

488

AN XY:

724424

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000805

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000442

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.000721

Gnomad4 OTH exome

AF:

0.000582

GnomAD4 genome

AF:

0.000690

AC:

105

AN:

152224

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.000521

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000357

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Propionic acidemia

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

PCCB: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

5.9

DANN

Benign

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000058

dbscSNV1_RF

Benign

0.0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over