Variant summary

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

The ENST00000237596.7(PKD2):c.2398A>C(p.Met800Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,614,092 control chromosomes in the GnomAD database, including 38 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M800T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0051 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 33 hom. )

Consequence

PKD2
ENST00000237596.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 1.49

Publications

18 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=0.0069056153).

BP6

Variant 4-88067937-A-C is Benign according to our data. Variant chr4-88067937-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 219985.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00511 (778/152282) while in subpopulation SAS AF = 0.0118 (57/4828). AF 95% confidence interval is 0.00936. There are 5 homozygotes in GnomAd4. There are 384 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000237596.7. 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.2398A>C	p.Met800Leu	missense	Exon 13 of 15	NP_000288.1
PKD2	NM_001440544.1		c.2173A>C	p.Met725Leu	missense	Exon 12 of 14	NP_001427473.1
PKD2	NR_156488.2		n.2376A>C		non_coding_transcript_exon	Exon 12 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PKD2	ENST00000237596.7	TSL:1 MANE Select	c.2398A>C	p.Met800Leu	missense	Exon 13 of 15	ENSP00000237596.2
PKD2	ENST00000502363.1	TSL:5	c.652A>C	p.Met218Leu	missense	Exon 6 of 8	ENSP00000425289.1
PKD2	ENST00000508588.5	TSL:2	c.652A>C	p.Met218Leu	missense	Exon 8 of 10	ENSP00000427131.1

Frequencies

GnomAD3 genomes

AF:

0.00511

AC:

778

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00717

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00655

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0120

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00292

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00487

AC:

1222

AN:

251060

AF XY:

0.00523

show subpopulations

Gnomad AFR exome

AF:

0.00806

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00293

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00316

AC:

4625

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00358

AC XY:

2601

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00774

AC:

259

AN:

33478

American (AMR)

AF:

0.00427

AC:

191

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

535

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0114

AC:

985

AN:

86256

European-Finnish (FIN)

AF:

0.000337

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.0187

AC:

108

AN:

5768

European-Non Finnish (NFE)

AF:

0.00197

AC:

2187

AN:

1111972

Other (OTH)

AF:

0.00566

AC:

342

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

269

539

808

1078

1347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<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:

0.00511

AC:

778

AN:

152282

Hom.:

Cov.:

AF XY:

0.00516

AC XY:

384

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00717

AC:

298

AN:

41556

American (AMR)

AF:

0.00654

AC:

100

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.0118

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00293

AC:

199

AN:

68030

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

129

172

215

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:

0.00438

Hom.:

Bravo

AF:

0.00536

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00480

AC:

583

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00456

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Autosomal dominant polycystic kidney disease (2)

not provided (2)

Polycystic kidney disease 2 (2)

Joubert syndrome 7 (1)

Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.14

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0069

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

PhyloP100

1.5

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.11

REVEL

Uncertain

0.40

Sift

Benign

0.67

Sift4G

Benign

0.94

Polyphen

0.0

Vest4

0.25

MutPred

0.49

Gain of glycosylation at S804 (P = 2e-04)

MVP

0.95

MPC

0.14

ClinPred

0.0022

GERP RS

3.1

Varity_R

0.046

gMVP

0.13

Mutation Taster

=97/3

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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rs2234917

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over