rs567482892

chr16-2091453-G-Achr16-2091453-G-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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.86

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

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 1768 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1768 AN: 148720 Hom.: 23 Cov.: 33

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.: 2 AF XY: 0.0156 AC XY: 74 AN XY: 4752

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.: 32 AF XY: 0.0203 AC XY: 10666 AN XY: 524320

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.: 23 Cov.: 33 AF XY: 0.0116 AC XY: 841 AN XY: 72568

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.: 4

Bravo AF: 0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:7

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)	-	- -

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	- -

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 “N/A” 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. -

not provided Benign:1

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) -

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

Other links and lift over

dbSNP: rs567482892; hg19: chr16-2141454; COSMIC: COSV99239592; COSMIC: COSV99239592;