13-100235868-A-G

Variant names:

• chr13-100235868-A-G
• rs538229
• NM_000282.4:c.627A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 5.13
• Publications: 15 publications found

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

ACMG classification

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 CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar as Benign. Clinvar id is 198708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-100235868-A-G is described in CliVar 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	c.627A>G	p.Ala209Ala	synonymous_variant	Exon 8 of 24	ENST00000376285.6	NP_000273.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21555 AN: 152104 Hom.: 1677 Cov.: 32

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

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.: 27 AF XY: 0.165 AC XY: 119037 AN XY: 721788

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

GnomAD4 genome AF: 0.142 AC: 21567 AN: 152222 Hom.: 1677 Cov.: 32 AF XY: 0.137 AC XY: 10167 AN XY: 74424

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: 58 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: 65 AN: 294

European-Non Finnish (NFE) AF: 0.178 AC: 12083 AN: 68000

Other (OTH) AF: 0.146 AC: 308 AN: 2114

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

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	11
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)

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

Other links and lift over

dbSNP: rs538229; hg19: chr13-100888122; COSMIC: COSV66191930;