rs148496347

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS1

The NM_001009944.3(PKD1):c.6665C>T(p.Ala2222Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,608,720 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2222T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00089 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 1 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 2.63

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 -7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001009944.3

BP4

Computational evidence support a benign effect (MetaRNN=0.03919947).

BP6

Variant 16-2108502-G-A is Benign according to our data. Variant chr16-2108502-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447995.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000893 (136/152310) while in subpopulation NFE AF = 0.00173 (118/68012). AF 95% confidence interval is 0.00148. There are 1 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.6665C>T	p.Ala2222Val	missense_variant	Exon 15 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.6665C>T	p.Ala2222Val	missense_variant	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes

AF:

0.000894

AC:

136

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00173

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000659

AC:

157

AN:

238062

AF XY:

0.000640

show subpopulations

Gnomad AFR exome

AF:

0.0000699

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.000307

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000242

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.000687

GnomAD4 exome

AF:

0.00140

AC:

2042

AN:

1456410

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

980

AN XY:

724540

show subpopulations

African (AFR)

AF:

0.000360

AC:

AN:

33378

American (AMR)

AF:

0.000179

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86154

European-Finnish (FIN)

AF:

0.000450

AC:

AN:

51150

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00175

AC:

1947

AN:

1111228

Other (OTH)

AF:

0.000751

AC:

AN:

59936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

120

240

359

479

599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.000893

AC:

136

AN:

152310

Hom.:

Cov.:

AF XY:

0.000873

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41572

American (AMR)

AF:

0.000196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00173

AC:

118

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00112

Hom.:

Bravo

AF:

0.000744

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00165

AC:

ExAC

AF:

0.000481

AC:

EpiCase

AF:

0.00142

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 18, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PKD1 c.6665C>T (p.Ala2222Val) 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 0.00066 in 238062 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.6665C>T 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: 447995). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Oct 28, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Polycystic kidney disease, adult type

Benign:2

Nov 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 06, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKD1: BP4, BS1, BS2 -

Inborn genetic diseases

Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.6665C>T (p.A2222V) alteration is located in exon 15 (coding exon 15) of the PKD1 gene. This alteration results from a C to T substitution at nucleotide position 6665, causing the alanine (A) at amino acid position 2222 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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.Ala2222Val variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, GeneInsight COGR, PKD1-LOVD and PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs148496347) as â€šÃ„ÃºNAâ€šÃ„Ã¹, ADPKD Mutation Database (classified as likely neutral), the 1000 Genomes Project in 4 of 5000 chromosomes (frequency: 0.0008), the NHLBI GO Exome Sequencing Project in 14 of 8480 European American alleles, the Exome Aggregation Consortium database (March 14, 2016) in 49 of 106856 chromosomes (freq. 0.0005) in the following populations: European in 48 of 57726 chromosomes (freq. 0.0008), African in 1 of 7870 chromosomes (freq. 0.0001), but was not seen in Asian, Finish, Latino and Other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. 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.Ala2222 residue is conserved across mammals and other organisms, however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest that the variant may impact the protein; this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -

PKD1-related disorder

Benign:1

Dec 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

0.098

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.71

T;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.039

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

2.0

M;M

PhyloP100

2.6

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.10

Sift

Benign

0.13

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.30

B;P

Vest4

0.21

MVP

0.81

ClinPred

0.022

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.041

gMVP

0.68

Mutation Taster

=46/54

disease causing

(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