rs189277711

Variant names:

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.6927C>T(p.Gly2309Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,553,324 control chromosomes in the GnomAD database, including 308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 33)

Exomes 𝑓: 0.018 ( 284 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.39

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=-0.8).

BP6

Variant 16-2108021-G-A is Benign according to our data. Variant chr16-2108021-G-A is described in ClinVar as Benign. ClinVar VariationId is 256994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.39 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0138 (2097/152288) while in subpopulation NFE AF = 0.0195 (1323/68004). AF 95% confidence interval is 0.0186. There are 24 homozygotes in GnomAd4. There are 1040 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.6927C>T	p.Gly2309Gly	synonymous_variant	Exon 16 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.6927C>T	p.Gly2309Gly	synonymous_variant	Exon 16 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

2097

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0369

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0131

AC:

2000

AN:

152096

AF XY:

0.0130

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00482

Gnomad ASJ exome

AF:

0.00522

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0315

Gnomad NFE exome

AF:

0.0197

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.0184

AC:

25727

AN:

1401036

Hom.:

284

Cov.:

AF XY:

0.0180

AC XY:

12434

AN XY:

691940

show subpopulations

African (AFR)

AF:

0.00292

AC:

AN:

31898

American (AMR)

AF:

0.00584

AC:

211

AN:

36124

Ashkenazi Jewish (ASJ)

AF:

0.00503

AC:

127

AN:

25232

East Asian (EAS)

AF:

0.0000275

AC:

AN:

36328

South Asian (SAS)

AF:

0.00704

AC:

563

AN:

79952

European-Finnish (FIN)

AF:

0.0331

AC:

1560

AN:

47104

Middle Eastern (MID)

AF:

0.00835

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.0206

AC:

22298

AN:

1082322

Other (OTH)

AF:

0.0145

AC:

840

AN:

58006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1297

2594

3890

5187

6484

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.0138

AC:

2097

AN:

152288

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1040

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00366

AC:

152

AN:

41568

American (AMR)

AF:

0.0101

AC:

154

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00580

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0369

AC:

392

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0195

AC:

1323

AN:

68004

Other (OTH)

AF:

0.0109

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

101

203

304

406

507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0152

Hom.:

Bravo

AF:

0.0119

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Jul 24, 2024

Athena Diagnostics

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

- -

Oct 17, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11967008, 11857740, 10854095) -

Polycystic kidney disease, adult type

Benign:1

Mar 23, 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.Gly2309Gly variant was identified in 17 of 732 proband chromosomes (frequency: 0.023) from individuals or families with ADPKD or renal disease, and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011, Garcia-Gonzalez 2007, McCluskey 2002, Rossetti 2012). The above studies determined this variant to be classified as a polymorphism based on either it being a synonymous variant, in silico analysis or interspecies conservation. The p.Gly2309Gly variant was identified in the dbSNP (ID: rs189277711) with unknown clinical significance with a minor allele frequency 0.0082 (41 of 5000 chromosomes in 1000 Genome Project). In the NHLBI Exome Sequencing Project, the variant was identified in 119 of 7256 alleles (frequency: 0.0164) in European Americans and 10 of 3486 African Americans (frequency: 0.00286). The variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 214 of 15790 alleles, 5 of which are homozygous (frequency: 0.0135) or 6 of 56 of European (Finnish), 138 of 5652 European (Non-Finnish), 8 of 380 Latino, 7 of 1120 African, 54 of 7844 South Asians, 1 of 168 other alleles and was not found in East Asians. The variant was identified in the ADPKD Mutation Database and classified as likely neutral. The c.6927C>T variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a location change of a cryptic 5â€šÃ„Ã´ splice donor site; this is not very predictive of pathogenicity. The p.Gly2309Gly 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 this variant was identified by our laboratory as co-occurring with pathogenic PKD1 variants in two different families with polycystic kidney disease (PKD1, EXON43, c.11798_11810del, p.Leu3933ArgfsX8 and c.2215C>T, p.Gln739X), increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant meets our criteria to be classified as benign. -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.34

(source)

DANN

Benign

0.86

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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