rs149056734

Positions:

chr16-2102188-G-A

Variant summary

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

The ENST00000262304.9(PKD1):c.9270C>T(p.Val3090=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,507,574 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 5 hom., cov: 32)

Exomes 𝑓: 0.011 ( 175 hom. )

Consequence

PKD1
ENST00000262304.9 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.666

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 16-2102188-G-A is Benign according to our data. Variant chr16-2102188-G-A is described in ClinVar as [Benign]. Clinvar id is 257041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2102188-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.666 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00747 (1135/151862) while in subpopulation NFE AF= 0.0118 (802/67998). AF 95% confidence interval is 0.0111. There are 5 homozygotes in gnomad4. There are 490 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.9270C>T	p.Val3090=	synonymous_variant	26/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.9270C>T	p.Val3090=	synonymous_variant	26/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00749

AC:

1136

AN:

151744

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00518

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.00614

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00764

GnomAD3 exomes

AF:

0.0101

AC:

1437

AN:

142816

Hom.:

AF XY:

0.0108

AC XY:

832

AN XY:

76978

show subpopulations

Gnomad AFR exome

AF:

0.00210

Gnomad AMR exome

AF:

0.00711

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00797

Gnomad FIN exome

AF:

0.00675

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0110

AC:

14857

AN:

1355712

Hom.:

175

Cov.:

AF XY:

0.0108

AC XY:

7350

AN XY:

678004

show subpopulations

Gnomad4 AFR exome

AF:

0.00239

Gnomad4 AMR exome

AF:

0.00549

Gnomad4 ASJ exome

AF:

0.0108

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00771

Gnomad4 FIN exome

AF:

0.00677

Gnomad4 NFE exome

AF:

0.0122

Gnomad4 OTH exome

AF:

0.0121

GnomAD4 genome

AF:

0.00747

AC:

1135

AN:

151862

Hom.:

Cov.:

AF XY:

0.00660

AC XY:

490

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.00221

Gnomad4 AMR

AF:

0.00517

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00726

Gnomad4 FIN

AF:

0.00614

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.00756

Alfa

AF:

0.0113

Hom.:

Bravo

AF:

0.00714

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	This variant is associated with the following publications: (PMID: 17574468, 22008521, 22383692, 11571556) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PKD1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

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

- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 20, 2020

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Val3090Val variant was identified as a polymorphism in 8 of 804 proband chromosomes (frequency: 0.010) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2012, Bouba 2001). The variant was also identified in dbSNP (ID: rs149056734) as â€šÃ„ÃºWith unknown alleleâ€šÃ„Ã¹, with a minor allele frequency of 0.0062 (31 of 5000 chromosomes in 1000 Genomes Project). The variant was identified in the NHLBI Exome Sequencing Project in 47 of 5946 European Americans and 4 of 2224 African American chromosomes. This variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 292 of 16060 chromosomes (frequency: 0.018 or 5 of 876 African , 19 of 508 Latino , 187 of 5858 European (Non-Finnish), 74 of 7872 South Asians, 5 of 90 Finnish and 2 of 156 other chromosomes and was not in found East Asian populations. The variant was identified in GeneInsight by one submitter and classified as benign. The variant was also identified in the PKD Mutation Database and classified as likely neutral. The p.Val3090Val 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 addition, this variant was identified in one individual from our laboratory as co-occurring with a pathogenic variant in PKD1 (c.7137C>G, p.Tyr2379X), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Benign, criteria provided, single submitter

research

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

Jan 01, 2019

- -

PKD1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

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

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.1

DANN

Benign

0.45

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