4-88007816-G-C

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.83G>C(p.Arg28Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,173,158 control chromosomes in the GnomAD database, including 56,509 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R28W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 4977 hom., cov: 32)

Exomes 𝑓: 0.31 ( 51532 hom. )

Consequence

PKD2
NM_000297.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.853

Publications

27 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=0.0023896992).

BP6

Variant 4-88007816-G-C is Benign according to our data. Variant chr4-88007816-G-C is described in ClinVar as Benign. ClinVar VariationId is 92798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000297.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PKD2	NM_000297.4	MANE Select	c.83G>C	p.Arg28Pro	missense	Exon 1 of 15	NP_000288.1
PKD2	NM_001440544.1		c.83G>C	p.Arg28Pro	missense	Exon 1 of 14	NP_001427473.1
PKD2	NR_156488.2		n.182G>C		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PKD2	ENST00000237596.7	TSL:1 MANE Select	c.83G>C	p.Arg28Pro	missense	Exon 1 of 15	ENSP00000237596.2
PKD2	ENST00000927447.1		c.83G>C	p.Arg28Pro	missense	Exon 1 of 15	ENSP00000597506.1
PKD2	ENST00000927448.1		c.83G>C	p.Arg28Pro	missense	Exon 1 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

34796

AN:

148556

Hom.:

4976

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.355

Gnomad AMR

AF:

0.220

Gnomad ASJ

AF:

0.272

Gnomad EAS

AF:

0.00157

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.337

Gnomad MID

AF:

0.252

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.246

GnomAD2 exomes

AF:

0.377

AC:

345

AN:

916

AF XY:

0.379

show subpopulations

Gnomad AFR exome

AF:

0.750

Gnomad AMR exome

AF:

0.276

Gnomad ASJ exome

AF:

0.500

Gnomad FIN exome

AF:

0.524

Gnomad NFE exome

AF:

0.385

Gnomad OTH exome

AF:

0.444

GnomAD4 exome

AF:

0.310

AC:

317470

AN:

1024494

Hom.:

51532

Cov.:

AF XY:

0.310

AC XY:

150572

AN XY:

485552

show subpopulations

African (AFR)

AF:

0.0944

AC:

1930

AN:

20450

American (AMR)

AF:

0.183

AC:

1180

AN:

6442

Ashkenazi Jewish (ASJ)

AF:

0.273

AC:

3127

AN:

11470

East Asian (EAS)

AF:

0.000920

AC:

AN:

20662

South Asian (SAS)

AF:

0.173

AC:

3430

AN:

19786

European-Finnish (FIN)

AF:

0.357

AC:

6547

AN:

18334

Middle Eastern (MID)

AF:

0.247

AC:

643

AN:

2606

European-Non Finnish (NFE)

AF:

0.328

AC:

290251

AN:

885716

Other (OTH)

AF:

0.265

AC:

10343

AN:

39028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

10335

20670

31005

41340

51675

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11142

22284

33426

44568

55710

<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:

0.234

AC:

34790

AN:

148664

Hom.:

4977

Cov.:

AF XY:

0.232

AC XY:

16839

AN XY:

72508

show subpopulations

African (AFR)

AF:

0.103

AC:

4254

AN:

41146

American (AMR)

AF:

0.219

AC:

3283

AN:

14980

Ashkenazi Jewish (ASJ)

AF:

0.272

AC:

933

AN:

3426

East Asian (EAS)

AF:

0.00157

AC:

AN:

5090

South Asian (SAS)

AF:

0.165

AC:

794

AN:

4812

European-Finnish (FIN)

AF:

0.337

AC:

3141

AN:

9310

Middle Eastern (MID)

AF:

0.250

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.322

AC:

21478

AN:

66628

Other (OTH)

AF:

0.243

AC:

502

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1335

2670

4004

5339

6674

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

338

676

1014

1352

1690

<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:

0.175

Hom.:

409

Bravo

AF:

0.214

TwinsUK

AF:

0.322

AC:

1195

ALSPAC

AF:

0.324

AC:

1248

ExAC

AF:

0.0532

AC:

189

Asia WGS

AF:

0.0790

AC:

258

AN:

3246

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Autosomal dominant polycystic kidney disease (2)

not provided (2)

Polycystic kidney disease 2 (2)

Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

PhyloP100

0.85

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.40

REVEL

Benign

0.046

Sift

Uncertain

0.012

Sift4G

Benign

0.29

Polyphen

0.15

Vest4

0.084

MPC

0.77

ClinPred

0.037

GERP RS

0.55

PromoterAI

0.035

Neutral

(source)

Varity_R

0.21

gMVP

0.31

Mutation Taster

=82/18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over