Genetic Variant PKD1:p.Arg3972Arg (chr16-2090971-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001009944.3(PKD1):c.11916C>T(p.Arg3972Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0298 in 1,543,072 control chromosomes in the GnomAD database, including 825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R3972R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 58 hom., cov: 34)

Exomes 𝑓: 0.031 ( 767 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.650

Publications

7 publications found

Variant links:

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 Gene-Disease associations (from GenCC):

autosomal dominant polycystic kidney disease
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
polycystic kidney disease 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
autosomal recessive polycystic kidney disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Caroli disease
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

PKD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 16-2090971-G-A is Benign according to our data. Variant chr16-2090971-G-A is described in ClinVar as Benign. ClinVar VariationId is 256909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.65 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0216 (3291/152196) while in subpopulation NFE AF = 0.0355 (2410/67972). AF 95% confidence interval is 0.0343. There are 58 homozygotes in GnomAd4. There are 1549 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 58 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.11916C>T	p.Arg3972Arg	synonymous	Exon 43 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.11913C>T	p.Arg3971Arg	synonymous	Exon 43 of 46	NP_000287.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PKD1	ENST00000262304.9	TSL:1 MANE Select	c.11916C>T	p.Arg3972Arg	synonymous	Exon 43 of 46	ENSP00000262304.4
PKD1	ENST00000423118.5	TSL:1	c.11913C>T	p.Arg3971Arg	synonymous	Exon 43 of 46	ENSP00000399501.1
PKD1	ENST00000561668.5	TSL:3	n.*440C>T		non_coding_transcript_exon	Exon 4 of 4	ENSP00000461391.1

Frequencies

GnomAD3 genomes

AF:

0.0216

AC:

3289

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00584

Gnomad AMI

AF:

0.0473

Gnomad AMR

AF:

0.00864

Gnomad ASJ

AF:

0.0144

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00765

Gnomad FIN

AF:

0.0314

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0355

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0203

AC:

2806

AN:

138110

AF XY:

0.0208

show subpopulations

Gnomad AFR exome

AF:

0.00553

Gnomad AMR exome

AF:

0.00722

Gnomad ASJ exome

AF:

0.0154

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0426

Gnomad NFE exome

AF:

0.0350

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0307

AC:

42693

AN:

1390876

Hom.:

767

Cov.:

AF XY:

0.0302

AC XY:

20774

AN XY:

687362

show subpopulations

African (AFR)

AF:

0.00447

AC:

143

AN:

31990

American (AMR)

AF:

0.00748

AC:

272

AN:

36350

Ashkenazi Jewish (ASJ)

AF:

0.0149

AC:

375

AN:

25146

East Asian (EAS)

AF:

0.0000828

AC:

AN:

36214

South Asian (SAS)

AF:

0.0113

AC:

909

AN:

80586

European-Finnish (FIN)

AF:

0.0392

AC:

1341

AN:

34198

Middle Eastern (MID)

AF:

0.00387

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.0353

AC:

38222

AN:

1082588

Other (OTH)

AF:

0.0242

AC:

1406

AN:

58118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

2794

5588

8381

11175

13969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1442

2884

4326

5768

7210

<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:

0.0216

AC:

3291

AN:

152196

Hom.:

Cov.:

AF XY:

0.0208

AC XY:

1549

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00583

AC:

242

AN:

41526

American (AMR)

AF:

0.00863

AC:

132

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5170

South Asian (SAS)

AF:

0.00828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0314

AC:

333

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0355

AC:

2410

AN:

67972

Other (OTH)

AF:

0.0180

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

175

350

524

699

874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0149

Hom.:

Bravo

AF:

0.0193

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Polycystic kidney disease, adult type

Benign:2

May 30, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 08, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 03, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10987650, 15772804)

Autosomal dominant polycystic kidney disease

Benign:1

Jan 01, 2019

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.6

(source)

DANN

Benign

0.88

PhyloP100

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over