rs117078377

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000297.4(PKD2):c.568G>A(p.Ala190Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,511,924 control chromosomes in the GnomAD database, including 3,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A190A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.030 ( 429 hom., cov: 32)

Exomes 𝑓: 0.025 ( 2622 hom. )

Consequence

PKD2
NM_000297.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.51

Publications

25 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:

ENSG00000286618 (HGNC:):

ENSG00000286618 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002696067).

BP6

Variant 4-88008301-G-A is Benign according to our data. Variant chr4-88008301-G-A is described in ClinVar as Benign. ClinVar VariationId is 92796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4 link	c.568G>A	p.Ala190Thr	missense_variant	Exon 1 of 15	ENST00000237596.7	NP_000288.1	Q13563-1Q9UEU6
PKD2	NM_001440544.1 link	c.568G>A	p.Ala190Thr	missense_variant	Exon 1 of 14		NP_001427473.1
PKD2	NR_156488.2 link	n.667G>A		non_coding_transcript_exon_variant	Exon 1 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PKD2	ENST00000237596.7 link	c.568G>A	p.Ala190Thr	missense_variant	Exon 1 of 15	1	NM_000297.4	ENSP00000237596.2	Q13563-1
PKD2	ENST00000506727.1 link	n.70G>A		non_coding_transcript_exon_variant	Exon 1 of 4	4
ENSG00000286618	ENST00000662475.1 link	n.112+65C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0298

AC:

4535

AN:

152046

Hom.:

434

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00432

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.0328

Gnomad EAS

AF:

0.384

Gnomad SAS

AF:

0.0842

Gnomad FIN

AF:

0.0636

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.0315

GnomAD2 exomes

AF:

0.0631

AC:

6927

AN:

109856

AF XY:

0.0638

show subpopulations

Gnomad AFR exome

AF:

0.00280

Gnomad AMR exome

AF:

0.0246

Gnomad ASJ exome

AF:

0.0367

Gnomad EAS exome

AF:

0.438

Gnomad FIN exome

AF:

0.0596

Gnomad NFE exome

AF:

0.0128

Gnomad OTH exome

AF:

0.0413

GnomAD4 exome

AF:

0.0254

AC:

34475

AN:

1359764

Hom.:

2622

Cov.:

AF XY:

0.0268

AC XY:

17982

AN XY:

670572

show subpopulations

African (AFR)

AF:

0.00294

AC:

AN:

28894

American (AMR)

AF:

0.0247

AC:

828

AN:

33522

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

856

AN:

24562

East Asian (EAS)

AF:

0.331

AC:

11163

AN:

33708

South Asian (SAS)

AF:

0.0727

AC:

5564

AN:

76510

European-Finnish (FIN)

AF:

0.0633

AC:

2105

AN:

33240

Middle Eastern (MID)

AF:

0.0395

AC:

158

AN:

3998

European-Non Finnish (NFE)

AF:

0.0107

AC:

11426

AN:

1068596

Other (OTH)

AF:

0.0404

AC:

2290

AN:

56734

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1640

3280

4920

6560

8200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

578

1156

1734

2312

2890

<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:

0.0297

AC:

4525

AN:

152160

Hom.:

429

Cov.:

AF XY:

0.0349

AC XY:

2593

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00431

AC:

179

AN:

41568

American (AMR)

AF:

0.0220

AC:

337

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0328

AC:

114

AN:

3472

East Asian (EAS)

AF:

0.383

AC:

1950

AN:

5090

South Asian (SAS)

AF:

0.0839

AC:

405

AN:

4830

European-Finnish (FIN)

AF:

0.0636

AC:

675

AN:

10606

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0117

AC:

793

AN:

67972

Other (OTH)

AF:

0.0326

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

188

375

563

750

938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0188

Hom.:

Bravo

AF:

0.0279

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0135

AC:

ExAC

AF:

0.0351

AC:

833

Asia WGS

AF:

0.202

AC:

701

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17574468, 22008521, 22863349, 18837007, 11438989, 20981092, 15192819, 27894351) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Polycystic kidney disease 2

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 27, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The c.568G>A, p.Ala190Thr variant was identified in 6.32% of 645 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

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

Benign

0.16

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Benign

0.13

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

PhyloP100

1.5

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.57

REVEL

Benign

0.12

Sift

Benign

0.43

Sift4G

Benign

0.41

Polyphen

0.91

Vest4

0.056

MPC

0.30

ClinPred

0.050

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.32

Mutation Taster

=90/10

polymorphism (auto)

(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