rs150949575

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001009944.3(PKD1):c.9795C>T(p.Ser3265Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,564,930 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 6 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.306

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 16-2099989-G-A is Benign according to our data. Variant chr16-2099989-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 586309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2099989-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.306 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00235 (358/152362) while in subpopulation AMR AF= 0.00594 (91/15312). AF 95% confidence interval is 0.00496. There are 1 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 358 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.9795C>T	p.Ser3265Ser	synonymous_variant	Exon 29 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.9795C>T	p.Ser3265Ser	synonymous_variant	Exon 29 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

358

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00595

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00307

Gnomad OTH

AF:

0.00955

GnomAD3 exomes

AF:

0.00164

AC:

276

AN:

168488

Hom.:

AF XY:

0.00159

AC XY:

143

AN XY:

89986

show subpopulations

Gnomad AFR exome

AF:

0.000223

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.00117

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000115

Gnomad NFE exome

AF:

0.00243

Gnomad OTH exome

AF:

0.00236

GnomAD4 exome

AF:

0.00234

AC:

3308

AN:

1412568

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

1599

AN XY:

698584

show subpopulations

Gnomad4 AFR exome

AF:

0.000373

Gnomad4 AMR exome

AF:

0.00338

Gnomad4 ASJ exome

AF:

0.00150

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.000307

Gnomad4 NFE exome

AF:

0.00276

Gnomad4 OTH exome

AF:

0.00185

GnomAD4 genome

AF:

0.00235

AC:

358

AN:

152362

Hom.:

Cov.:

AF XY:

0.00205

AC XY:

153

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00594

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00307

Gnomad4 OTH

AF:

0.00945

Alfa

AF:

0.00210

Hom.:

Bravo

AF:

0.00283

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BP7 -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 09, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 04, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22383692, 17574468) -

not specified

Benign:1

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type

Benign:1

Feb 20, 2019

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.Ser3265= variant was identified in 3 of 530 proband chromosomes (frequency: 0.006) from individuals or families with ADPKD, and was not identified in 342 control chromosomes from healthy individuals (Garcia-Gonzalez 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs150949575) as â€šÃ„ÃºNAâ€šÃ„Ã¹, ADPKD Mutation Database (likely neutral), the 1000 Genomes Project in 6 of 5008 chromosomes (frequency: 0.001) the NHLBI GO Exome Sequencing Project in 22 of 8382 European American alleles (freq: 0.003) and 2 in 4268 African American alleles (freq: 0.0005), the genome Aggregation Database (beta, October 19th 2016) in 295 of 192204 chromosomes (freq. 0.002), the Exome Aggregation Consortium database (August 8th 2016) in 31 of 22232 chromosomes (freq. 0.0014) in the following populations: Latino in 2 of 592 chromosomes (freq. 0.003), European in 28 of 8570 chromosomes (freq. 0.003) and African in 1 of 2192 chromosomes (freq. 0.0005), but was not seen in East Asian, Finnish, other and South Asian populations, increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. In addition the variant was identified with a co-occurring pathogenic PKD1 variant (p.Trp1243X) by our laboratory in a patient with ADPKD, increasing the likelihood that the p.Ser3265=variant does not have clinical significance. The variant was not identified in HAPMAP, GeneInsight COGR, ClinVar, Clinvitae, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. The p.Ser3265= 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, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.6

DANN

Benign

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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