rs200185747

Positions:

Variant summary

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

The NM_000532.5(PCCB):c.49C>A(p.Leu17Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,589,370 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 3 hom. )

Consequence

PCCB
NM_000532.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 0.372

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063657463).

BP6

Variant 3-136250424-C-A is Benign according to our data. Variant chr3-136250424-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203883.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}. Variant chr3-136250424-C-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PCCB	NM_000532.5 linkuse as main transcript	c.49C>A	p.Leu17Met	missense_variant	1/15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2 linkuse as main transcript	c.49C>A	p.Leu17Met	missense_variant	1/16		NP_001171485.1
PCCB	XM_011512873.2 linkuse as main transcript	c.49C>A	p.Leu17Met	missense_variant	1/11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 linkuse as main transcript	c.49C>A	p.Leu17Met	missense_variant	1/15	1	NM_000532.5	ENSP00000251654	P2	P05166-1

Frequencies

GnomAD3 genomes

AF:

0.00159

AC:

242

AN:

152270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00295

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00153

AC:

313

AN:

204210

Hom.:

AF XY:

0.00151

AC XY:

168

AN XY:

111604

show subpopulations

Gnomad AFR exome

AF:

0.000511

Gnomad AMR exome

AF:

0.000496

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000842

Gnomad NFE exome

AF:

0.00310

Gnomad OTH exome

AF:

0.000983

GnomAD4 exome

AF:

0.00250

AC:

3598

AN:

1436982

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

1684

AN XY:

712736

show subpopulations

Gnomad4 AFR exome

AF:

0.000393

Gnomad4 AMR exome

AF:

0.000510

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000966

Gnomad4 NFE exome

AF:

0.00312

Gnomad4 OTH exome

AF:

0.00133

GnomAD4 genome

AF:

0.00159

AC:

242

AN:

152388

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00295

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.00144

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000686

AC:

ESP6500EA

AF:

0.00317

AC:

ExAC

AF:

0.00144

AC:

173

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2020	This variant is associated with the following publications: (PMID: 12757933, 10447268, 27896094) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Propionic acidemia

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 16, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2022	Variant summary: PCCB c.49C>A (p.Leu17Met) results in a conservative amino acid change located in the mitochondrial leader sequence (Chloupkova_2002) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 204310 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCCB causing Propionic Acidemia phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.49C>A has been reported in the literature in individuals affected with Propionic Acidemia (Muro_1999, Kruszka_2014). These reports do not provide unequivocal conclusions about association of the variant with Propionic Acidemia. At least one co-occurrence with another pathogenic variant has been reported (PCCB c.790dupG, p.Asp264Glyfs*3, Muro_1999), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

PCCB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.33

T;.;.;T;T;T;.;.;.;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.76

T;T;T;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.0064

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.0

N;.;.;.;.;.;.;.;N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.39

N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.59

Sift

Benign

0.062

T;T;T;D;T;T;T;D;D;D;D

Sift4G

Benign

0.24

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.036

B;.;.;.;.;.;.;B;.;.;.

Vest4

0.27

MVP

0.67

MPC

0.097

ClinPred

0.019

GERP RS

0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.077

gMVP

0.44

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

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