Genetic Variant NM_018492.4:c.822G>C (chr8-27810452-C-G) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_018492.4(PBK):c.822G>C(p.Ala274Ala) 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.154

Publications

19 publications found

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:

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

ESCO2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
PBK	NM_018492.4 link	c.822G>C	p.Ala274Ala	synonymous_variant	Exon 8 of 8	ENST00000301905.9	NP_060962.2	Q96KB5-1V9HWH0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PBK	ENST00000301905.9 link	c.822G>C	p.Ala274Ala	synonymous_variant	Exon 8 of 8	1	NM_018492.4	ENSP00000301905.4		Q96KB5-1

Frequencies

GnomAD3 genomes

AF:

0.435

AC:

65961

AN:

151786

Hom.:

14501

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.429

AC:

107490

AN:

250276

AF XY:

0.434

show subpopulations

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 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.:

AF XY:

0.434

AC XY:

313892

AN XY:

723616

show subpopulations

African (AFR)

AF:

0.413

AC:

13758

AN:

33284

American (AMR)

AF:

0.359

AC:

16004

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.589

AC:

15342

AN:

26060

East Asian (EAS)

AF:

0.380

AC:

15048

AN:

39618

South Asian (SAS)

AF:

0.420

AC:

36160

AN:

86060

European-Finnish (FIN)

AF:

0.462

AC:

24635

AN:

53330

Middle Eastern (MID)

AF:

0.553

AC:

3173

AN:

5734

European-Non Finnish (NFE)

AF:

0.432

AC:

477191

AN:

1104746

Other (OTH)

AF:

0.454

AC:

27264

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

15748

31497

47245

62994

78742

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14450

28900

43350

57800

72250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.434

AC:

65988

AN:

151904

Hom.:

14498

Cov.:

AF XY:

0.437

AC XY:

32419

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.421

AC:

17435

AN:

41414

American (AMR)

AF:

0.423

AC:

6450

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.600

AC:

2082

AN:

3470

East Asian (EAS)

AF:

0.384

AC:

1985

AN:

5168

South Asian (SAS)

AF:

0.414

AC:

1998

AN:

4822

European-Finnish (FIN)

AF:

0.470

AC:

4949

AN:

10528

Middle Eastern (MID)

AF:

0.534

AC:

157

AN:

294

European-Non Finnish (NFE)

AF:

0.437

AC:

29692

AN:

67936

Other (OTH)

AF:

0.467

AC:

981

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1899

3799

5698

7598

9497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

622

1244

1866

2488

3110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

DANN

Benign

0.66

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over