rs2575313

chr16-2109404-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.352

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 4749 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.5763G>A	p.Leu1921=	synonymous_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.5763G>A	p.Leu1921=	synonymous_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4749 AN: 152236 Hom.: 113 Cov.: 33

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

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.: 35 AF XY: 0.0423 AC XY: 30484 AN XY: 720262

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.: 33 AF XY: 0.0315 AC XY: 2345 AN XY: 74492

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.: 31

Bravo AF: 0.0260

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0451

EpiControl AF: 0.0417

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

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)	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 26, 2018	- -
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

Other links and lift over

dbSNP: rs2575313; hg19: chr16-2159405;