Genetic Variant PCCB:c.763+10C>A (chr3-136293874-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000532.5(PCCB):c.763+10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,305,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

PCCB
NM_000532.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0910

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: Myriad Women’s Health, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

PCCB links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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.763+10C>A		intron	N/A	NP_000523.2	P05166-1
	PCCB	NM_001178014.2		c.823+10C>A		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.763+10C>A	intron	N/A	ENSP00000251654.4	P05166-1
PCCB	ENST00000471595.5	TSL:1	c.763+10C>A	intron	N/A	ENSP00000417549.1	E9PDR0
PCCB	ENST00000478469.5	TSL:1	c.763+10C>A	intron	N/A	ENSP00000420759.1	E7ENC1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000153

AC:

AN:

1305098

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

657786

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30506

American (AMR)

AF:

0.00

AC:

AN:

44550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25192

East Asian (EAS)

AF:

0.00

AC:

AN:

38996

South Asian (SAS)

AF:

0.00

AC:

AN:

82996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5464

European-Non Finnish (NFE)

AF:

0.00000206

AC:

AN:

968964

Other (OTH)

AF:

0.00

AC:

AN:

55214

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.61

PhyloP100

0.091

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Computational scores

Splicing

Publications

Other links and lift over