dbSNP rs146927771: PCCA:p.Ala310Gly (chr13-100273210-C-G) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_000282.4(PCCA):c.929C>G(p.Ala310Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000656 in 1,612,482 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A310V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 2 hom. )

Consequence

PCCA
NM_000282.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 4.92

Publications

5 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: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

PCCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000282.4

BP4

Computational evidence support a benign effect (MetaRNN=0.014012933).

BP6

Variant 13-100273210-C-G is Benign according to our data. Variant chr13-100273210-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 788170.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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	HGVSp	Effect	Exon Rank	Protein	UniProt
PCCA	NM_000282.4	MANE Select	c.929C>G	p.Ala310Gly	missense	Exon 12 of 24	NP_000273.2	P05165-1
PCCA	NM_001352605.2		c.929C>G	p.Ala310Gly	missense	Exon 12 of 23	NP_001339534.1
PCCA	NM_001127692.3		c.851C>G	p.Ala284Gly	missense	Exon 11 of 23	NP_001121164.1	P05165-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCCA	ENST00000376285.6	TSL:1 MANE Select	c.929C>G	p.Ala310Gly	missense	Exon 12 of 24	ENSP00000365462.1	P05165-1
PCCA	ENST00000881637.1		c.1052C>G	p.Ala351Gly	missense	Exon 13 of 25	ENSP00000551696.1
PCCA	ENST00000881640.1		c.1034C>G	p.Ala345Gly	missense	Exon 13 of 25	ENSP00000551699.1

Frequencies

GnomAD3 genomes

AF:

0.000612

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000705

AC:

177

AN:

251176

AF XY:

0.000773

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000766

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000660

AC:

964

AN:

1460326

Hom.:

Cov.:

AF XY:

0.000692

AC XY:

503

AN XY:

726574

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33440

American (AMR)

AF:

0.000134

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00597

AC:

156

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000656

AC:

729

AN:

1110718

Other (OTH)

AF:

0.000779

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000611

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41532

American (AMR)

AF:

0.000327

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

67994

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000994

Hom.:

Bravo

AF:

0.000578

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000692

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Propionic acidemia (4)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.014

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.1

PhyloP100

4.9

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.33

Sift

Benign

0.069

Sift4G

Benign

0.18

Polyphen

0.043

Vest4

0.31

MVP

0.92

MPC

0.18

ClinPred

0.036

GERP RS

3.8

Varity_R

0.072

gMVP

0.46

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over