8-27811070-C-G

Position:

• chr8-27811070-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018492.4(PBK):​c.660G>C​(p.Glu220Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,613,190 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.019 (104 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (97 hom.)
• Consequence: PBK NM_018492.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.56

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]

ESCO2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014903843).
• BP6: Variant 8-27811070-C-G is Benign according to our data. Variant chr8-27811070-C-G is described in ClinVar as [Benign]. Clinvar id is 776305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PBK	NM_018492.4	c.660G>C	p.Glu220Asp	missense_variant	7/8	ENST00000301905.9	NP_060962.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PBK	ENST00000301905.9	c.660G>C	p.Glu220Asp	missense_variant	7/8	1	NM_018492.4	ENSP00000301905.4

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2920 AN: 152198 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.0665

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00517 AC: 1299 AN: 251350 Hom.: 52 AF XY: 0.00373 AC XY: 507 AN XY: 135830

Gnomad AFR exome AF: 0.0707

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00206 AC: 3006 AN: 1460874 Hom.: 97 Cov.: 30 AF XY: 0.00176 AC XY: 1276 AN XY: 726790

Gnomad4 AFR exome AF: 0.0711

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000738

Gnomad4 OTH exome AF: 0.00535

GnomAD4 genome AF: 0.0192 AC: 2928 AN: 152316 Hom.: 104 Cov.: 32 AF XY: 0.0183 AC XY: 1365 AN XY: 74480

Gnomad4 AFR AF: 0.0665

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00517 Hom.: 8

Bravo AF: 0.0222

ESP6500AA AF: 0.0679 AC: 299

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00604 AC: 733

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.80	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.27	N;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.85	N;N
REVEL	Benign	0.094
Sift	Benign	0.21	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.040	B;.
Vest4		0.089
MutPred		0.12		Loss of disorder (P = 0.1389);.;
MVP		0.29
MPC		0.094
ClinPred		0.014	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.20
gMVP		0.52

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

Other links and lift over

dbSNP: rs17057901; hg19: chr8-27668587;