8-27822404-A-G

Position:

chr8-27822404-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018492.4(PBK):c.380T>C(p.Ile127Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PBK
NM_018492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.96

Variant links:

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]

PBK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PBK	NM_018492.4 linkuse as main transcript	c.380T>C	p.Ile127Thr	missense_variant	5/8	ENST00000301905.9	NP_060962.2	Q96KB5-1V9HWH0
PBK	NM_001278945.2 linkuse as main transcript	c.380T>C	p.Ile127Thr	missense_variant	5/8		NP_001265874.1	Q96KB5-2
PBK	NM_001363040.2 linkuse as main transcript	c.380T>C	p.Ile127Thr	missense_variant	5/8		NP_001349969.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PBK	ENST00000301905.9 linkuse as main transcript	c.380T>C	p.Ile127Thr	missense_variant	5/8	1	NM_018492.4	ENSP00000301905.4	Q96KB5-1
PBK	ENST00000522944.5 linkuse as main transcript	c.380T>C	p.Ile127Thr	missense_variant	5/8	2		ENSP00000428489.1	Q96KB5-2
PBK	ENST00000521226.2 linkuse as main transcript	c.278T>C	p.Ile93Thr	missense_variant	5/6	3		ENSP00000427892.2	E5RFX4
PBK	ENST00000524266.1 linkuse as main transcript	n.153-1710T>C		intron_variant		5		ENSP00000428438.1	E5RIE1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250892

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135614

show subpopulations

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:

0.0000983

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460854

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.380T>C (p.I127T) alteration is located in exon 5 (coding exon 4) of the PBK gene. This alteration results from a T to C substitution at nucleotide position 380, causing the isoleucine (I) at amino acid position 127 to be replaced by a threonine (T). 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

0.73

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.6

M;M;.

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.3

D;D;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.010

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.92

MutPred

0.77

Gain of disorder (P = 0.017);Gain of disorder (P = 0.017);.;

MVP

0.94

MPC

0.53

ClinPred

0.98

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.62

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

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