Genetic Variant PCCA:c.468+211A>G (chr13-100157551-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000282.4(PCCA):c.468+211A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,254 control chromosomes in the GnomAD database, including 1,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.14 ( 1659 hom., cov: 33)

Consequence

PCCA
NM_000282.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.176

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 13-100157551-A-G is Benign according to our data. Variant chr13-100157551-A-G is described in ClinVar as Benign. ClinVar VariationId is 669947.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000282.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PCCA	NM_000282.4	MANE Select	c.468+211A>G	intron	N/A	NP_000273.2
PCCA	NM_001352605.2		c.468+211A>G	intron	N/A	NP_001339534.1
PCCA	NM_001127692.3		c.390+211A>G	intron	N/A	NP_001121164.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PCCA	ENST00000376285.6	TSL:1 MANE Select	c.468+211A>G	intron	N/A	ENSP00000365462.1
PCCA	ENST00000376286.8	TSL:2	c.390+211A>G	intron	N/A	ENSP00000365463.4
PCCA	ENST00000376279.7	TSL:2	c.468+211A>G	intron	N/A	ENSP00000365456.3

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21630

AN:

152136

Hom.:

1654

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.0896

Gnomad ASJ

AF:

0.0746

Gnomad EAS

AF:

0.0574

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.178

Gnomad OTH

AF:

0.138

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.142

AC:

21645

AN:

152254

Hom.:

1659

Cov.:

AF XY:

0.139

AC XY:

10371

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.120

AC:

5003

AN:

41564

American (AMR)

AF:

0.0897

AC:

1372

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0746

AC:

259

AN:

3472

East Asian (EAS)

AF:

0.0575

AC:

298

AN:

5184

South Asian (SAS)

AF:

0.177

AC:

855

AN:

4824

European-Finnish (FIN)

AF:

0.117

AC:

1237

AN:

10592

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.178

AC:

12113

AN:

67994

Other (OTH)

AF:

0.143

AC:

302

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

954

1908

2861

3815

4769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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:

0.141

Hom.:

284

Bravo

AF:

0.136

Asia WGS

AF:

0.141

AC:

493

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.5

(source)

DANN

Benign

0.86

PhyloP100

0.18

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over