chr8-27818230-A-G

Variant names:

• chr8-27818230-A-G
• rs10503818
• NM_018492.4:c.595+2335T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018492.4(PBK):​c.595+2335T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 152,122 control chromosomes in the GnomAD database, including 13,578 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 0.42 (13578 hom., cov: 33)
• Consequence: PBK NM_018492.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.106
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Roberts-SC phocomelia syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Roberts syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PBK	NM_018492.4	c.595+2335T>C		intron_variant	Intron 6 of 7	ENST00000301905.9	NP_060962.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBK	ENST00000301905.9	c.595+2335T>C		intron_variant	Intron 6 of 7	1	NM_018492.4	ENSP00000301905.4
PBK	ENST00000522944.5	c.595+2335T>C		intron_variant	Intron 6 of 7	2		ENSP00000428489.1
PBK	ENST00000524266.1	n.*90+2335T>C		intron_variant	Intron 4 of 5	5		ENSP00000428438.1

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63306 AN: 152004 Hom.: 13554 Cov.: 33

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.403

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.417 AC: 63387 AN: 152122 Hom.: 13578 Cov.: 33 AF XY: 0.416 AC XY: 30911 AN XY: 74374

African (AFR) AF: 0.365 AC: 15131 AN: 41486

American (AMR) AF: 0.493 AC: 7537 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 931 AN: 3472

East Asian (EAS) AF: 0.616 AC: 3181 AN: 5166

South Asian (SAS) AF: 0.432 AC: 2088 AN: 4830

European-Finnish (FIN) AF: 0.371 AC: 3922 AN: 10582

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29167 AN: 67980

Other (OTH) AF: 0.407 AC: 859 AN: 2108

Alfa AF: 0.438 Hom.: 2506

Bravo AF: 0.427

Asia WGS AF: 0.548 AC: 1901 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.6
DANN	Benign	0.72
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10503818; hg19: chr8-27675747;