16-2114809-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001009944.3(PKD1):c.2214C>G(p.Pro738Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00672 in 979,188 control chromosomes in the GnomAD database, including 311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 196 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 115 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.527

Publications

1 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=-0.86).

BP6

Variant 16-2114809-G-C is Benign according to our data. Variant chr16-2114809-G-C is described in ClinVar as Benign. ClinVar VariationId is 256931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.527 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.2214C>G	p.Pro738Pro	synonymous_variant	Exon 11 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.2214C>G	p.Pro738Pro	synonymous_variant	Exon 11 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes

AF:

0.0264

AC:

4007

AN:

151976

Hom.:

196

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0915

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00858

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000648

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.00639

AC:

799

AN:

125016

AF XY:

0.00476

show subpopulations

Gnomad AFR exome

AF:

0.0977

Gnomad AMR exome

AF:

0.00618

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000351

Gnomad OTH exome

AF:

0.00256

GnomAD4 exome

AF:

0.00311

AC:

2572

AN:

827098

Hom.:

115

Cov.:

AF XY:

0.00250

AC XY:

1063

AN XY:

424462

show subpopulations

African (AFR)

AF:

0.0925

AC:

1839

AN:

19874

American (AMR)

AF:

0.00708

AC:

234

AN:

33040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20734

East Asian (EAS)

AF:

0.00

AC:

AN:

32904

South Asian (SAS)

AF:

0.000108

AC:

AN:

64806

European-Finnish (FIN)

AF:

0.0000307

AC:

AN:

32524

Middle Eastern (MID)

AF:

0.00358

AC:

AN:

3072

European-Non Finnish (NFE)

AF:

0.000280

AC:

163

AN:

581164

Other (OTH)

AF:

0.00813

AC:

317

AN:

38980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

158

316

474

632

790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.0264

AC:

4010

AN:

152090

Hom.:

196

Cov.:

AF XY:

0.0250

AC XY:

1859

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0913

AC:

3790

AN:

41508

American (AMR)

AF:

0.00857

AC:

131

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000648

AC:

AN:

67910

Other (OTH)

AF:

0.0199

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

182

363

545

726

908

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:

0.00162

Hom.:

Bravo

AF:

0.0297

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 27, 2025

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 29, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Oct 11, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 26, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17574468, 22008521)

Polycystic kidney disease, adult type

Benign:1

Jun 02, 2020

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 PKD1 p.Pro738Pro variant was identified in 1 of 74 proband chromosomes (frequency: 0.014) from unrelated individuals or families with ADPKD, and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011). The variant is listed in the dbSNP database (ID#: rs543166733), however no frequency information was provided. This variant is also listed in the 1000 Genomes Project in 174 of 5014 chromosomes (frequency: 0.035). The variant was identified in the Exome Aggregation Consortium database (March 14 2106) in 49 of 7068 chromosomes (freq. 0.007) in the following populations: African in 46 (1 homozygous) of 494 chromosomes (freq. 0.09), Latino in 2 of 142 chromosomes (freq. 0.01), other in 1 of 88 chromosomes (freq. 0.01), but was not seen in East Asian, Finish, European (Non-Finnish) and South Asian populations, increasing the likelihood this could be a low frequency benign variant. We cannot be certain that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant is identified In GeneInsight COGR 1x as benign and by the ADPKD Mutation Database 4x as likely neutral. The p.Pro738Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as benign.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.048

(source)

DANN

Benign

0.45

PhyloP100

-0.53

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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