rs200185747

Positions:

• chr3-136250424-C-A
• chr3-136250424-C-G
• chr3-136250424-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (3 hom.)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.372

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 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=5, 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	UniProt
PCCB	NM_000532.5	c.49C>A	p.Leu17Met	missense_variant	1/15	ENST00000251654.9
PCCB	NM_001178014.2	c.49C>A	p.Leu17Met	missense_variant	1/16
PCCB	XM_011512873.2	c.49C>A	p.Leu17Met	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCCB	ENST00000251654.9	c.49C>A	p.Leu17Met	missense_variant	1/15	1	NM_000532.5	P2

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152270 Hom.: 2 Cov.: 33

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.: 0 AF XY: 0.00151 AC XY: 168 AN XY: 111604

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.: 3 Cov.: 31 AF XY: 0.00236 AC XY: 1684 AN XY: 712736

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.: 2 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74520

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.: 0

Bravo AF: 0.00144

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000686 AC: 3

ESP6500EA AF: 0.00317 AC: 27

ExAC AF: 0.00144 AC: 173

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -

Propionic acidemia Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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, 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, criteria provided, single submitter

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	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	14
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	N
LIST_S2	Benign	0.76	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.0064	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.0	N;.;.;.;.;.;.;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.45	T
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	T
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

Other links and lift over

dbSNP: rs200185747; hg19: chr3-135969266; COSMIC: COSV52443558; COSMIC: COSV52443558;