8-27828125-T-C

Position:

• chr8-27828125-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018492.4(PBK):​c.132A>G​(p.Val44Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,553,634 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (20 hom.)
• Consequence: PBK NM_018492.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.205

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 8-27828125-T-C is Benign according to our data. Variant chr8-27828125-T-C is described in ClinVar as [Benign]. Clinvar id is 776306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.205 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00991 (1510/152332) while in subpopulation AFR AF= 0.0337 (1400/41576). AF 95% confidence interval is 0.0322. There are 21 homozygotes in gnomad4. There are 719 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PBK	NM_018492.4	c.132A>G	p.Val44Val	synonymous_variant	3/8	ENST00000301905.9	NP_060962.2
PBK	NM_001278945.2	c.132A>G	p.Val44Val	synonymous_variant	3/8		NP_001265874.1
PBK	NM_001363040.2	c.132A>G	p.Val44Val	synonymous_variant	3/8		NP_001349969.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PBK	ENST00000301905.9	c.132A>G	p.Val44Val	synonymous_variant	3/8	1	NM_018492.4	ENSP00000301905.4
PBK	ENST00000522944.5	c.132A>G	p.Val44Val	synonymous_variant	3/8	2		ENSP00000428489.1
PBK	ENST00000521226.2	c.30A>G	p.Val10Val	synonymous_variant	3/6	3		ENSP00000427892.2
PBK	ENST00000524266.1	n.132A>G		non_coding_transcript_exon_variant	3/6	5		ENSP00000428438.1

Frequencies

GnomAD3 genomes AF: 0.00993 AC: 1511 AN: 152214 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00293 AC: 735 AN: 251158 Hom.: 7 AF XY: 0.00214 AC XY: 290 AN XY: 135804

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00122 AC: 1709 AN: 1401302 Hom.: 20 Cov.: 24 AF XY: 0.00108 AC XY: 757 AN XY: 700778

Gnomad4 AFR exome AF: 0.0328

Gnomad4 AMR exome AF: 0.00278

Gnomad4 ASJ exome AF: 0.000311

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000356

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00991 AC: 1510 AN: 152332 Hom.: 21 Cov.: 32 AF XY: 0.00965 AC XY: 719 AN XY: 74492

Gnomad4 AFR AF: 0.0337

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00530 Hom.: 5

Bravo AF: 0.0114

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.0
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35230929; hg19: chr8-27685642;