dbSNP rs147654263: PKD2:p.Arg807Gln (chr4-88067959-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000297.4(PKD2):c.2420G>A(p.Arg807Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,613,880 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 12 hom. )

Consequence

PKD2
NM_000297.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 9.31

Publications

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

PKD2 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=0.008992344).

BP6

Variant 4-88067959-G-A is Benign according to our data. Variant chr4-88067959-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00302 (460/152236) while in subpopulation AMR AF = 0.00432 (66/15292). AF 95% confidence interval is 0.00348. There are 3 homozygotes in GnomAd4. There are 290 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

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	UniProt
PKD2	NM_000297.4	MANE Select	c.2420G>A	p.Arg807Gln	missense	Exon 13 of 15	NP_000288.1	Q13563-1
PKD2	NM_001440544.1		c.2195G>A	p.Arg732Gln	missense	Exon 12 of 14	NP_001427473.1
PKD2	NR_156488.2		n.2398G>A		non_coding_transcript_exon	Exon 12 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKD2	ENST00000237596.7	TSL:1 MANE Select	c.2420G>A	p.Arg807Gln	missense	Exon 13 of 15	ENSP00000237596.2	Q13563-1
PKD2	ENST00000927447.1		c.2417G>A	p.Arg806Gln	missense	Exon 13 of 15	ENSP00000597506.1
PKD2	ENST00000927448.1		c.2321G>A	p.Arg774Gln	missense	Exon 12 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

459

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0187

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00213

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00300

AC:

754

AN:

251136

AF XY:

0.00309

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.00457

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0164

Gnomad NFE exome

AF:

0.00233

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00279

AC:

4076

AN:

1461644

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

2028

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33476

American (AMR)

AF:

0.00215

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00421

AC:

110

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0168

AC:

895

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00252

AC:

2802

AN:

1111806

Other (OTH)

AF:

0.00263

AC:

159

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

217

434

652

869

1086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00302

AC:

460

AN:

152236

Hom.:

Cov.:

AF XY:

0.00390

AC XY:

290

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41550

American (AMR)

AF:

0.00432

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0187

AC:

198

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00215

AC:

146

AN:

68020

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

102

127

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:

0.00212

Hom.:

Bravo

AF:

0.00221

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00277

AC:

336

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00213

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Polycystic kidney disease 2 (3)

Autosomal dominant polycystic kidney disease (2)

not provided (2)

Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0090

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

1.9

PhyloP100

9.3

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.56

REVEL

Uncertain

0.44

Sift

Benign

0.23

Sift4G

Benign

0.23

Polyphen

1.0

Vest4

0.89

MVP

0.86

MPC

0.67

ClinPred

0.044

GERP RS

5.7

Varity_R

0.10

gMVP

0.36

Mutation Taster

=51/49

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over