rs145343957

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000297.4(PKD2):c.2411G>A(p.Ser804Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 1,614,094 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 2 hom. )

Consequence

PKD2
NM_000297.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: 9.31

Publications

5 publications found

Variant links:

Genes affected

PKD2 (HGNC:9009): (polycystin 2, transient receptor potential cation channel) This gene encodes a member of the polycystin protein family. The encoded protein is a multi-pass membrane protein that functions as a calcium permeable cation channel, and is involved in calcium transport and calcium signaling in renal epithelial cells. This protein interacts with polycystin 1, and they may be partners in a common signaling cascade involved in tubular morphogenesis. Mutations in this gene are associated with autosomal dominant polycystic kidney disease type 2. [provided by RefSeq, Mar 2011]

PKD2 Gene-Disease associations (from GenCC):

autosomal dominant polycystic kidney disease
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
polycystic kidney disease 2
Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

PKD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010641098).

BP6

Variant 4-88067950-G-A is Benign according to our data. Variant chr4-88067950-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289403.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00263 (400/152294) while in subpopulation AFR AF = 0.00816 (339/41556). AF 95% confidence interval is 0.00744. There are 3 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4 link	c.2411G>A	p.Ser804Asn	missense_variant	Exon 13 of 15	ENST00000237596.7	NP_000288.1	Q13563-1Q9UEU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 link	c.2411G>A	p.Ser804Asn	missense_variant	Exon 13 of 15	1	NM_000297.4	ENSP00000237596.2		Q13563-1

Frequencies

GnomAD3 genomes

AF:

0.00263

AC:

400

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00818

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.000848

AC:

213

AN:

251112

AF XY:

0.000737

show subpopulations

Gnomad AFR exome

AF:

0.00720

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000313

AC:

458

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

215

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00624

AC:

209

AN:

33476

American (AMR)

AF:

0.00199

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000827

AC:

AN:

1111960

Other (OTH)

AF:

0.00101

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00263

AC:

400

AN:

152294

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

208

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00816

AC:

339

AN:

41556

American (AMR)

AF:

0.00275

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68024

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000875

Hom.:

Bravo

AF:

0.00297

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00840

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000832

AC:

101

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKD2: BS1, BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 12, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease 2

Uncertain:1Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 21, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 11, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKD2 p.Ser804Asn variant was identified in 1 of 404 proband chromosomes (frequency: 0.0025) from individuals or families with Autosomal Dominant PKD (Rossetti 2007). The variant was also identified in dbSNP (ID: rs145343957) as â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, in ClinVar (as benign by EGL Genetic Diagnostics and Invitae, and as uncertain significance by ARUP Laboratories), LOVD 3.0 (1x as "indeterminate"), and ADPKD Mutation Database. The variant was not identified in PKD1-LOVD. The variant was identified in control databases in 277 of 276842 chromosomes (1 homozygous) at a frequency of 0.001001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 179 of 24034 chromosomes (freq: 0.007), Other in 17 of 6460 chromosomes (freq: 0.003), Latino in 65 of 34394 chromosomes (freq: 0.002), European (Non-Finnish) in 16 of 126422 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The mutation is located within the consensus kinase recognition sequence; a functional study showed the p.Ser804Asn variant abolished Ser801 phosphorylation, indicating its likely physiological significance, and this study therefore classified the variant as pathogenic (Streets 2010). The p.Ser804 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Autosomal dominant polycystic kidney disease

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;T;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

D;.;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.1

M;.;.

PhyloP100

9.3

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.73

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.082

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.60

MVP

0.69

MPC

0.59

ClinPred

0.025

GERP RS

5.7

Varity_R

0.18

gMVP

0.36

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over