rs2294092

Positions:

• chr8-27810452-C-G
• chr8-27810452-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_018492.4(PBK):​c.822G>C​(p.Ala274=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 1,605,480 control chromosomes in the GnomAD database, including 152,074 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.43 (14498 hom., cov: 32)
  • Exomes 𝑓: 0.43 (137576 hom.)
• Consequence: PBK NM_018492.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154

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]

ESCO2 (HGNC:27230): (establishment of sister chromatid cohesion N-acetyltransferase 2) This gene encodes a protein that may have acetyltransferase activity and may be required for the establishment of sister chromatid cohesion during the S phase of mitosis. Mutations in this gene have been associated with Roberts syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP7: Synonymous conserved (PhyloP=-0.154 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PBK	NM_018492.4	c.822G>C	p.Ala274=	synonymous_variant	8/8	ENST00000301905.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PBK	ENST00000301905.9	c.822G>C	p.Ala274=	synonymous_variant	8/8	1	NM_018492.4	P1
ESCO2	ENST00000522378.5	c.*862-853C>G		intron_variant, NMD_transcript_variant		1
PBK	ENST00000522944.5	c.855G>C	p.Ala285=	synonymous_variant	8/8	2
PBK	ENST00000524266.1	c.*317G>C		3_prime_UTR_variant, NMD_transcript_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.435 AC: 65961 AN: 151786 Hom.: 14501 Cov.: 32

Gnomad AFR AF: 0.421

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.469

GnomAD3 exomes AF: 0.429 AC: 107490 AN: 250276 Hom.: 23615 AF XY: 0.434 AC XY: 58811 AN XY: 135382

Gnomad AFR exome AF: 0.418

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.591

Gnomad EAS exome AF: 0.396

Gnomad SAS exome AF: 0.416

Gnomad FIN exome AF: 0.471

Gnomad NFE exome AF: 0.442

Gnomad OTH exome AF: 0.460

GnomAD4 exome AF: 0.432 AC: 628575 AN: 1453576 Hom.: 137576 Cov.: 29 AF XY: 0.434 AC XY: 313892 AN XY: 723616

Gnomad4 AFR exome AF: 0.413

Gnomad4 AMR exome AF: 0.359

Gnomad4 ASJ exome AF: 0.589

Gnomad4 EAS exome AF: 0.380

Gnomad4 SAS exome AF: 0.420

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.432

Gnomad4 OTH exome AF: 0.454

GnomAD4 genome AF: 0.434 AC: 65988 AN: 151904 Hom.: 14498 Cov.: 32 AF XY: 0.437 AC XY: 32419 AN XY: 74246

Gnomad4 AFR AF: 0.421

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.600

Gnomad4 EAS AF: 0.384

Gnomad4 SAS AF: 0.414

Gnomad4 FIN AF: 0.470

Gnomad4 NFE AF: 0.437

Gnomad4 OTH AF: 0.467

Alfa AF: 0.415 Hom.: 3964

Bravo AF: 0.430

Asia WGS AF: 0.391 AC: 1366 AN: 3478

EpiCase AF: 0.470

EpiControl AF: 0.469

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.2
DANN	Benign	0.66

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: rs2294092; hg19: chr8-27667969; COSMIC: COSV57273020; COSMIC: COSV57273020;