3-136328780-A-T

Position:

• chr3-136328780-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000532.5(PCCB):​c.1421A>T​(p.Lys474Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PCCB NM_000532.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.19

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue N6-acetyllysine; alternate (size 0) in uniprot entity PCCB_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCCB	NM_000532.5	c.1421A>T	p.Lys474Ile	missense_variant	14/15	ENST00000251654.9	NP_000523.2
PCCB	NM_001178014.2	c.1481A>T	p.Lys494Ile	missense_variant	15/16		NP_001171485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCCB	ENST00000251654.9	c.1421A>T	p.Lys474Ile	missense_variant	14/15	1	NM_000532.5	ENSP00000251654.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251154 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;.;.;D;D;D;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.4	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		0.32	B;.;.;.;.;.;.;P;.
Vest4		0.56
MutPred		0.60		Loss of methylation at K474 (P = 0.0084);.;.;.;.;.;.;Loss of methylation at K474 (P = 0.0084);.;
MVP		0.95
MPC		0.58
ClinPred		0.98	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs145628302; hg19: chr3-136047622;