rs2575313

Positions:

chr16-2109404-C-T

Variant summary

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

The NM_001009944.3(PKD1):c.5763G>A(p.Leu1921=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,600,104 control chromosomes in the GnomAD database, including 1,705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 113 hom., cov: 33)

Exomes 𝑓: 0.043 ( 1592 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.352

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=-0.57).

BP6

Variant 16-2109404-C-T is Benign according to our data. Variant chr16-2109404-C-T is described in ClinVar as [Benign]. Clinvar id is 256981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109404-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.352 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0312 (4748/152354) while in subpopulation NFE AF= 0.0469 (3190/68032). AF 95% confidence interval is 0.0455. There are 113 homozygotes in gnomad4. There are 2345 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4748 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.5763G>A	p.Leu1921=	synonymous_variant	15/46	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.5763G>A	p.Leu1921=	synonymous_variant	15/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0312

AC:

4749

AN:

152236

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00810

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0203

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00351

Gnomad FIN

AF:

0.0740

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0469

Gnomad OTH

AF:

0.0220

GnomAD3 exomes

AF:

0.0308

AC:

7168

AN:

232416

Hom.:

154

AF XY:

0.0311

AC XY:

4007

AN XY:

128964

show subpopulations

Gnomad AFR exome

AF:

0.00648

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0161

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00356

Gnomad FIN exome

AF:

0.0742

Gnomad NFE exome

AF:

0.0469

Gnomad OTH exome

AF:

0.0325

GnomAD4 exome

AF:

0.0433

AC:

62753

AN:

1447750

Hom.:

1592

Cov.:

AF XY:

0.0423

AC XY:

30484

AN XY:

720262

show subpopulations

Gnomad4 AFR exome

AF:

0.00635

Gnomad4 AMR exome

AF:

0.0165

Gnomad4 ASJ exome

AF:

0.0172

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00424

Gnomad4 FIN exome

AF:

0.0756

Gnomad4 NFE exome

AF:

0.0500

Gnomad4 OTH exome

AF:

0.0361

GnomAD4 genome

AF:

0.0312

AC:

4748

AN:

152354

Hom.:

113

Cov.:

AF XY:

0.0315

AC XY:

2345

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00808

Gnomad4 AMR

AF:

0.0203

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.0740

Gnomad4 NFE

AF:

0.0469

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.0382

Hom.:

Bravo

AF:

0.0260

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0451

EpiControl

AF:

0.0417

ClinVar

Significance: Benign

Submissions summary: Benign:9

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, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2019	- -

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.Leu1921Leu variant was identified in 39 of 842 proband chromosomes (frequency: 0.046) from individuals or families with ADPKD or renal disease, and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011, Garcia-Gonzalez 2007, McCluskey 2002, Rossetti 2012, Thomas 1999). All the above studies have identified the variant as a polymorphism. The p.Leu1921Leu variant was identified in the dbSNP (ID: rs2575313) with unknown clinical significance with a minor allele frequency 0.012 (60 of 5000 chromosomes in 1000 Genome Project). In the NHLBI Exome Sequencing Project (Exome Variant Server), the variant was identified in 387 of 8262 alleles (frequency: 0.05) in the European Americans and 39 of 4067 alleles in African Americans (Frequency: 0.01). The variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 3512 of 107304 chromosomes (frequency: 0.03) or 471 of 5522 of European (Finnish), 2749 of 58470 European (Non-Finnish), 151 of 10988 Latino, 61 of 7502 African, and 59 of 15918 South Asians chromosomes and was not found in East Asians. The variant was identified in the PKD Mutation Database and classified as likely neutral. The c.5763G>A variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a greater than 10% difference in splicing. The p.Leu1921Leu 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 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.5

DANN

Benign

0.85

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