rs199886085

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_000532.5(PCCB):c.654+3A>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000547 in 1,584,326 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 7 hom. )

Consequence

PCCB
NM_000532.5 splice_region, intron

Scores

Splicing: ADA: 0.9938

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.68

Publications

0 publications found

Variant links:

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]

PCCB Gene-Disease associations (from GenCC):

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

PCCB links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000532.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 3-136283950-A-C is Benign according to our data. Variant chr3-136283950-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529438.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000532.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCCB	NM_000532.5	MANE Select	c.654+3A>C		splice_region intron	N/A	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.714+3A>C		splice_region intron	N/A	NP_001171485.1	P05166-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PCCB	ENST00000251654.9	TSL:1 MANE Select	c.654+3A>C	splice_region intron	N/A	ENSP00000251654.4	P05166-1
PCCB	ENST00000471595.5	TSL:1	c.654+3A>C	splice_region intron	N/A	ENSP00000417549.1	E9PDR0
PCCB	ENST00000478469.5	TSL:1	c.654+3A>C	splice_region intron	N/A	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000999

AC:

251

AN:

251316

AF XY:

0.00128

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000281

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000564

AC:

808

AN:

1432020

Hom.:

Cov.:

AF XY:

0.000764

AC XY:

546

AN XY:

714354

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32894

American (AMR)

AF:

0.000224

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0000385

AC:

AN:

25972

East Asian (EAS)

AF:

0.00

AC:

AN:

39578

South Asian (SAS)

AF:

0.00646

AC:

554

AN:

85700

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.00384

AC:

AN:

5474

European-Non Finnish (NFE)

AF:

0.000169

AC:

183

AN:

1085070

Other (OTH)

AF:

0.000623

AC:

AN:

59350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000387

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68018

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000279

Hom.:

Bravo

AF:

0.000185

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Propionic acidemia (3)

not provided (2)

PCCB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

(source)

DANN

Benign

0.95

PhyloP100

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.68

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.68

Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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