rs77820367

Positions:

chr3-136298060-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000532.5(PCCB):c.872G>A(p.Cys291Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00179 in 1,614,132 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 5 hom. )

Consequence

PCCB
NM_000532.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.61

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 links:

PCCB (HGNC:):

PCCB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCB	NM_000532.5 linkuse as main transcript	c.872G>A	p.Cys291Tyr	missense_variant	8/15	ENST00000251654.9	NP_000523.2	P05166-1
PCCB	NM_001178014.2 linkuse as main transcript	c.932G>A	p.Cys311Tyr	missense_variant	9/16		NP_001171485.1	P05166-2
PCCB	XM_011512873.2 linkuse as main transcript	c.872G>A	p.Cys291Tyr	missense_variant	8/11		XP_011511175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9 linkuse as main transcript	c.872G>A	p.Cys291Tyr	missense_variant	8/15	1	NM_000532.5	ENSP00000251654.4		P05166-1

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

215

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00133

AC:

335

AN:

251462

Hom.:

AF XY:

0.00136

AC XY:

185

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00573

Gnomad NFE exome

AF:

0.00162

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.00183

AC:

2679

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

1265

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00509

Gnomad4 NFE exome

AF:

0.00205

Gnomad4 OTH exome

AF:

0.00174

GnomAD4 genome

AF:

0.00140

AC:

214

AN:

152314

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00518

Gnomad4 NFE

AF:

0.00190

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.00106

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00118

AC:

143

EpiCase

AF:

0.00229

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Propionic acidemia

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 26, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2023	BP5, PS3_supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2024	Has previously been reported in a patient with propionic acidemia who was heterozygous for C291Y and in whom a second variant in PCCB was not identified; however this patient was also homozygous for a pathogenic variant in the PCCA gene (PMID: 22033733); Expression studies of C291Y in E. coli reported that it is associated with significantly reduced enzyme activity; however, no wild-type controls were used for comparison (PMID: 22033733); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 25087612, 34426522, 34670123, 22033733, 24448499, 26740555, 27460824, 28050010, 29618726, 28719003, 36099812, 35132093) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 14, 2023

Variant summary: PCCB c.872G>A (p.Cys291Tyr) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxylase carboxyl transferase subunit beta (IPR034733) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 1614132 control chromosomes in the gnomAD database, including 5 homozygotes (gnomAD v4). This frequency is not significantly higher than estimated for a pathogenic variant in PCCB causing Propionic Acidemia (0.0018 vs 0.0025), allowing no conclusion about variant significance. c.872G>A has been reported at a heterozygous state in one individual affected with Propionic Acidemia, whose phenotypes may be fully explained by a co-occurring homozygous pathogenic variant in PCCA (c.1899+4_1899+7del) (Kraus_2012). This variant was also reported in unspecified individuals with idiopathic spontaneous pregnancy losses or individuals undertaking multiple-gene panel testing for CHD, TGA, heterotaxy, without strong evidence for causality (Blue_2022, Buonaiuto_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Propionic Acidemia. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 1.5% of normal activity in E. coli (Kraus_2012). The following publications have been ascertained in the context of this evaluation (PMID: 34670123, 35132093, 22033733). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Likely pathogenic, n=1, likely benign, n=1, VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;.;.;D;D;D;.;.;.;D

Eigen

Benign

0.17

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.014

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

1.6

L;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.8

D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.69

Sift

Benign

0.098

T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T;T

Polyphen

0.91

P;.;.;.;.;.;.;P;.;.

Vest4

0.78

MVP

0.98

MPC

0.33

ClinPred

0.060

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.40

Position offset: -7

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over