rs538229

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000282.4(PCCA):c.627A>G(p.Ala209Ala) variant causes a synonymous change. The variant allele was found at a frequency of 0.163 in 1,601,178 control chromosomes in the GnomAD database, including 22,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1677 hom., cov: 32)

Exomes 𝑓: 0.17 ( 21110 hom. )

Consequence

PCCA
NM_000282.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 5.13

Publications

15 publications found

Variant links:

Genes affected

PCCA (HGNC:8653): (propionyl-CoA carboxylase subunit alpha) The protein encoded by this gene is the alpha subunit of the heterodimeric mitochondrial enzyme Propionyl-CoA carboxylase. PCCA encodes the biotin-binding region of this enzyme. Mutations in either PCCA or PCCB (encoding the beta subunit) lead to an enzyme deficiency resulting in propionic acidemia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

PCCA Gene-Disease associations (from GenCC):

propionic acidemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen, Orphanet

PCCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 13-100235868-A-G is Benign according to our data. Variant chr13-100235868-A-G is described in ClinVar as [Benign]. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCCA	NM_000282.4 link	c.627A>G	p.Ala209Ala	synonymous_variant	Exon 8 of 24	ENST00000376285.6	NP_000273.2	P05165-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCCA	ENST00000376285.6 link	c.627A>G	p.Ala209Ala	synonymous_variant	Exon 8 of 24	1	NM_000282.4	ENSP00000365462.1		P05165-1

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21555

AN:

152104

Hom.:

1677

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.0934

Gnomad AMR

AF:

0.161

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.0112

Gnomad SAS

AF:

0.132

Gnomad FIN

AF:

0.0917

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.178

Gnomad OTH

AF:

0.146

GnomAD2 exomes

AF:

0.147

AC:

37067

AN:

251336

AF XY:

0.150

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.168

Gnomad ASJ exome

AF:

0.176

Gnomad EAS exome

AF:

0.00870

Gnomad FIN exome

AF:

0.0961

Gnomad NFE exome

AF:

0.176

Gnomad OTH exome

AF:

0.159

GnomAD4 exome

AF:

0.165

AC:

239420

AN:

1448956

Hom.:

21110

Cov.:

AF XY:

0.165

AC XY:

119037

AN XY:

721788

show subpopulations

African (AFR)

AF:

0.102

AC:

3382

AN:

33262

American (AMR)

AF:

0.167

AC:

7446

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

4511

AN:

26010

East Asian (EAS)

AF:

0.00614

AC:

243

AN:

39578

South Asian (SAS)

AF:

0.151

AC:

12985

AN:

85972

European-Finnish (FIN)

AF:

0.103

AC:

5521

AN:

53374

Middle Eastern (MID)

AF:

0.195

AC:

1119

AN:

5732

European-Non Finnish (NFE)

AF:

0.177

AC:

194724

AN:

1100354

Other (OTH)

AF:

0.158

AC:

9489

AN:

59980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

8174

16348

24522

32696

40870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6714

13428

20142

26856

33570

<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

AF:

0.142

AC:

21567

AN:

152222

Hom.:

1677

Cov.:

AF XY:

0.137

AC XY:

10167

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.105

AC:

4366

AN:

41540

American (AMR)

AF:

0.160

AC:

2450

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

539

AN:

3468

East Asian (EAS)

AF:

0.0112

AC:

AN:

5180

South Asian (SAS)

AF:

0.133

AC:

641

AN:

4828

European-Finnish (FIN)

AF:

0.0917

AC:

972

AN:

10598

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.178

AC:

12083

AN:

68000

Other (OTH)

AF:

0.146

AC:

308

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

950

1900

2850

3800

4750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

248

496

744

992

1240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.169

Hom.:

1652

Bravo

AF:

0.147

Asia WGS

AF:

0.0800

AC:

277

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 11, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Propionic acidemia

Benign:5

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 13, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PCCA c.627A>G (p.Ala209Ala) variant involves the alteration of a conserved nucleotide causing a synonymous change that 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 17901/121368 control chromosomes (1483 homozygotes) at a frequency of 0.1474936, which is approximately 43 times the estimated maximal expected allele frequency for a pathogenic PCCA variant (0.003446), strong evidence that this variant is a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over