rs567482892

Positions:

Variant summary

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

The NM_001009944.3(PKD1):c.11682C>T(p.Ser3894=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,236,480 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 0.012 ( 23 hom., cov: 33)

Exomes 𝑓: 0.021 ( 285 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.86

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:

PKD1-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

PKD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 16-2091453-G-A is Benign according to our data. Variant chr16-2091453-G-A is described in ClinVar as [Benign]. Clinvar id is 256908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2091453-G-A is described in Lovd as [Benign]. Variant chr16-2091453-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.86 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1768/148828) while in subpopulation NFE AF= 0.0194 (1293/66760). AF 95% confidence interval is 0.0185. There are 23 homozygotes in gnomad4. There are 841 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1768 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.11682C>T	p.Ser3894=	synonymous_variant	42/46	ENST00000262304.9	NP_001009944.3
PKD1-AS1	NR_135175.1 linkuse as main transcript	n.18G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.11682C>T	p.Ser3894=	synonymous_variant	42/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1768

AN:

148720

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00344

Gnomad AMI

AF:

0.0165

Gnomad AMR

AF:

0.00797

Gnomad ASJ

AF:

0.00205

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.0169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0194

Gnomad OTH

AF:

0.0107

GnomAD3 exomes

AF:

0.0179

AC:

126

AN:

7026

Hom.:

AF XY:

0.0156

AC XY:

AN XY:

4752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0286

Gnomad ASJ exome

AF:

0.00213

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000552

Gnomad FIN exome

AF:

0.0342

Gnomad NFE exome

AF:

0.0267

Gnomad OTH exome

AF:

0.00943

GnomAD4 exome

AF:

0.0206

AC:

22388

AN:

1087652

Hom.:

285

Cov.:

AF XY:

0.0203

AC XY:

10666

AN XY:

524320

show subpopulations

Gnomad4 AFR exome

AF:

0.00263

Gnomad4 AMR exome

AF:

0.0110

Gnomad4 ASJ exome

AF:

0.00326

Gnomad4 EAS exome

AF:

0.0000534

Gnomad4 SAS exome

AF:

0.00138

Gnomad4 FIN exome

AF:

0.0185

Gnomad4 NFE exome

AF:

0.0227

Gnomad4 OTH exome

AF:

0.0196

GnomAD4 genome

AF:

0.0119

AC:

1768

AN:

148828

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

841

AN XY:

72568

show subpopulations

Gnomad4 AFR

AF:

0.00343

Gnomad4 AMR

AF:

0.00796

Gnomad4 ASJ

AF:

0.00205

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00271

Gnomad4 FIN

AF:

0.0169

Gnomad4 NFE

AF:

0.0194

Gnomad4 OTH

AF:

0.0106

Alfa

AF:

0.0161

Hom.:

Bravo

AF:

0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 30, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2020	This variant is associated with the following publications: (PMID: 15772804, 17574468, 18837007, 22008521, 22383692, 24374109) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ser3894Ser variant was identified in 11 of 1112 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2012, Peltola 2005). The variant was also identified in dbSNP (ID: rs567482892) as â€šÃ„ÃºN/Aâ€šÃ„Ã¹ and the ADPKD Mutation Database (as likely neutral). This variant was identified in the 1000 Genomes Project in 21 of 5000 chromosomes (frequency: 0.004), the Exome Aggregation Consortium database (August 8, 2016) in 8 (1 homozygous) of 462 chromosomes (freq. 0.02) in the following populations: European in 5 of 40 chromosomes (freq. 0.13), Finnish in 1 of 2 chromosomes (freq. 0.5), Latino in 1 of 10 chromosomes (freq. 0.1), South Asian in 1 of 398 chromosomes (freq. 0.003), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Ser3894Ser 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. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In addition, the variant classified as a polymorphism by number of population and research studies (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2012, Peltola 2005). 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

-0.53

CADD

Benign

5.9

DANN

Benign

0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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