rs147788838

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001009944.3(PKD1):c.8713G>A(p.Val2905Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,605,844 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 18 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 2.37

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013485014).

BP6

Variant 16-2103344-C-T is Benign according to our data. Variant chr16-2103344-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257028.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr16-2103344-C-T is described in Lovd as [Likely_benign]. Variant chr16-2103344-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00179 (273/152284) while in subpopulation NFE AF= 0.00288 (196/68020). AF 95% confidence interval is 0.00255. There are 2 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 273 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8713G>A	p.Val2905Ile	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.8713G>A	p.Val2905Ile	missense_variant	Exon 23 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

273

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00288

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00170

AC:

407

AN:

238784

Hom.:

AF XY:

0.00169

AC XY:

222

AN XY:

131708

show subpopulations

Gnomad AFR exome

AF:

0.000907

Gnomad AMR exome

AF:

0.00195

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000409

Gnomad NFE exome

AF:

0.00277

Gnomad OTH exome

AF:

0.00253

GnomAD4 exome

AF:

0.00324

AC:

4714

AN:

1453560

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

2259

AN XY:

723358

show subpopulations

Gnomad4 AFR exome

AF:

0.000928

Gnomad4 AMR exome

AF:

0.00181

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000929

Gnomad4 FIN exome

AF:

0.000483

Gnomad4 NFE exome

AF:

0.00393

Gnomad4 OTH exome

AF:

0.00339

GnomAD4 genome

AF:

0.00179

AC:

273

AN:

152284

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

121

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000938

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00288

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00273

Hom.:

Bravo

AF:

0.00193

ESP6500AA

AF:

0.000952

AC:

ESP6500EA

AF:

0.00265

AC:

ExAC

AF:

0.00147

AC:

175

EpiCase

AF:

0.00382

EpiControl

AF:

0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Jan 25, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BS2 -

Polycystic kidney disease, adult type

Uncertain:1

Feb 26, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKD1 c.8713G>A; p.Val2905Ile variant (rs147788838) is reported in the literature as a benign polymorphism (Rossetti 2001). This variant is also reported in ClinVar (Variation ID: 257028), and is found in the general population with an overall allele frequency of 0.17% (457/270176 alleles, including a single homozygote) in the Genome Aggregation Database. The valine at codon 2905 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Val2905Ile variant is uncertain at this time. References: Rossetti S et al. Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. Am J Hum Genet. 2001 Jan;68(1):46-63. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely 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.Val2905Ile variant was identified as a polymorphism in the literature in a cohort of 131 patients with ADPKD however frequency information was not reported (Rossetti 2001). The variant was also identified in dbSNP (ID: rs147788838) as â€šÃ„ÃºNAâ€šÃ„Ã¹, and the ADPKD Mutation Database (classification â€šÃ„Ãºlikely neutralâ€šÃ„Ã¹) but not in Clinvitae, ClinVar, GeneInsight COGR, PKD1-LOVD, or PKD1-LOVD 3.0 databases. The variant was identified in the 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.0014); HAPMAP populations: AMR in 1 of 694 chromosomes (frequency: 0.0014), EUR in 5 of 1006 chromosomes (frequency: 0.005), and AFR in 1 of 1322 chromosomes (frequency: 0.0008); the NHLBI GO Exome Sequencing Project in 22 of 8316 European American alleles and in 4 of 4202 African American alleles; and in the Exome Aggregation Consortium database (March 14, 2016): 30 of 11356 alleles (frequency: 0.0026) in a Latino population, in 129 of 61572 alleles (1 homozygous, frequency: 0.0021) from a European (Non-Finnish) population, in 1 of 8386 alleles (frequency: 0.0001) from a East Asian population, in 6 of 8310 alleles (frequency: 0.0007) from an African population, in 3 of 16374 alleles (frequency: 0.0002) from a population of South Asian and in 2 of 6556 alleles (frequency: 0.0003) from a population of European (Finnish) individuals; it was not seen in â€šÃ„ÃºOtherâ€šÃ„Ã¹ population. The p.Val2905 residue is not conserved in mammals and the variant amino acid Ile is present in dog, increasing the likelihood that this variant does not have clinical significance. 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. This variant was identified in our laboratory in one individual with ADPKD and a co-occurring pathogenic variant in PKD1 (c.160_166dup, p.Leu56ProfsX60), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.68

T;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.9

L;L

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.39

N;N

REVEL

Benign

0.098

Sift

Benign

0.14

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.56

P;P

Vest4

0.34

MVP

0.73

ClinPred

0.0088

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.023

gMVP

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over