chr16-2103617-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.8440G>A(p.Gly2814Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,610,450 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G2814G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0062 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0075 ( 57 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.55

Publications

11 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 -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_001009944.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0081606805).

BP6

Variant 16-2103617-C-T is Benign according to our data. Variant chr16-2103617-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0062 (944/152302) while in subpopulation NFE AF = 0.00859 (584/68018). AF 95% confidence interval is 0.00801. There are 5 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8440G>A	p.Gly2814Arg	missense_variant	Exon 23 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.8440G>A	p.Gly2814Arg	missense_variant	Exon 23 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00621

AC:

945

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0171

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00858

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00611

AC:

1520

AN:

248758

AF XY:

0.00605

show subpopulations

Gnomad AFR exome

AF:

0.00163

Gnomad AMR exome

AF:

0.00417

Gnomad ASJ exome

AF:

0.000401

Gnomad EAS exome

AF:

0.000491

Gnomad FIN exome

AF:

0.0175

Gnomad NFE exome

AF:

0.00818

Gnomad OTH exome

AF:

0.00659

GnomAD4 exome

AF:

0.00747

AC:

10891

AN:

1458148

Hom.:

Cov.:

AF XY:

0.00714

AC XY:

5178

AN XY:

725392

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33402

American (AMR)

AF:

0.00490

AC:

219

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26126

East Asian (EAS)

AF:

0.000302

AC:

AN:

39694

South Asian (SAS)

AF:

0.000197

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.0166

AC:

862

AN:

52048

Middle Eastern (MID)

AF:

0.00290

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00841

AC:

9345

AN:

1111692

Other (OTH)

AF:

0.00628

AC:

378

AN:

60176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

672

1345

2017

2690

3362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.00620

AC:

944

AN:

152302

Hom.:

Cov.:

AF XY:

0.00665

AC XY:

495

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41584

American (AMR)

AF:

0.00719

AC:

110

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0171

AC:

182

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00859

AC:

584

AN:

68018

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

137

182

228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00445

Hom.:

Bravo

AF:

0.00544

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00828

AC:

ExAC

AF:

0.00553

AC:

665

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 18, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PKD1 c.8440G>A (p.Gly2814Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0061 in 248758 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease phenotype. To our knowledge, no occurrence of c.8440G>A in individuals affected with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 257021). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKD1: BS2 -

Mar 10, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17574468, 12007219, 24374109, 18837007) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Polycystic kidney disease, adult type

Benign:2

Sep 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 26, 2018

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:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKD1 p.Gly2814Arg variant was identified in 29 of 1202 proband chromosomes (frequency: 0.024) from individuals or families with ADPKD (Garcia-Gonzalez 2007, Inoue 2002, Rossetti 2001, Rossetti 2002, Rossetti 2012, Tan 2008). The variant was also identified in dbSNP (ID: rs149151043) as "With other allele ", ClinVar (classified as benign by ARUP and Prevention Genetics), LOVD 3.0 (2x as benign or with unknown effect), and in ADPKD Mutation Database (likely neutral). The variant was not identified in COGR, or PKD1-LOVD databases. The variant was identified in control databases in 1715 of 275482 chromosomes (7 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 34 of 23822 chromosomes (freq: 0.0014), Other in 43 of 6430 chromosomes (freq: 0.0066), Latino in 146 of 34410 chromosomes (freq: 0.004), European in 1016 of 125388 chromosomes (freq: 0.008), Ashkenazi Jewish in 4 of 10094 chromosomes (freq: 0.00039), East Asian in 9 of 18840 chromosomes (freq: 0.00047), Finnish in 458 of 25724 chromosomes (freq: 0.017), and South Asian in 5 of 30774 chromosomes (freq: 0.00016). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Gly2814 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, the variant was identified with a co-occurring pathogenic PKD1 or PKD2 variants (PKD1 p.Glu2810*, p.Ile3109fs*, c.7704-1G>T; and PKD2 p.Arg872*), increasing the likelihood that the p.Gly2814Arg variant does not have clinical significance (Garcia-Gonzalez 2007). 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 likely benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Jan 01, 2019

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

PKD1-related disorder

Benign:1

Sep 05, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.62

T;T

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L

PhyloP100

1.5

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.17

Sift

Benign

0.072

T;T

Sift4G

Uncertain

0.020

D;D

Polyphen

0.99

D;D

Vest4

0.63

MutPred

0.48

Loss of catalytic residue at G2814 (P = 0.021);Loss of catalytic residue at G2814 (P = 0.021);

MVP

0.74

ClinPred

0.013

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.068

gMVP

0.56

Mutation Taster

=80/20

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over