8-27822371-A-C

Position:

• chr8-27822371-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018492.4(PBK):​c.413T>G​(p.Phe138Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PBK NM_018492.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.96

Genes affected

PBK (HGNC:18282): (PDZ binding kinase) This gene encodes a serine/threonine protein kinase related to the dual specific mitogen-activated protein kinase kinase (MAPKK) family. Evidence suggests that mitotic phosphorylation is required for its catalytic activity. The encoded protein may be involved in the activation of lymphoid cells and support testicular functions, with a suggested role in the process of spermatogenesis. Overexpression of this gene has been implicated in tumorigenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PBK	NM_018492.4	c.413T>G	p.Phe138Cys	missense_variant	5/8	ENST00000301905.9	NP_060962.2
PBK	NM_001278945.2	c.413T>G	p.Phe138Cys	missense_variant	5/8		NP_001265874.1
PBK	NM_001363040.2	c.413T>G	p.Phe138Cys	missense_variant	5/8		NP_001349969.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PBK	ENST00000301905.9	c.413T>G	p.Phe138Cys	missense_variant	5/8	1	NM_018492.4	ENSP00000301905.4
PBK	ENST00000522944.5	c.413T>G	p.Phe138Cys	missense_variant	5/8	2		ENSP00000428489.1
PBK	ENST00000521226.2	c.311T>G	p.Phe104Cys	missense_variant	5/6	3		ENSP00000427892.2
PBK	ENST00000524266.1	n.153-1677T>G		intron_variant		5		ENSP00000428438.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461212 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726886

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.413T>G (p.F138C) alteration is located in exon 5 (coding exon 4) of the PBK gene. This alteration results from a T to G substitution at nucleotide position 413, causing the phenylalanine (F) at amino acid position 138 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.090	D
MutationAssessor	Pathogenic	3.0	M;M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.5	D;D;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.93
MutPred		0.76		Gain of catalytic residue at P137 (P = 0.0179);Gain of catalytic residue at P137 (P = 0.0179);.;
MVP		0.95
MPC		0.59
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.87
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-27679888;