rs117856830

chr16-2103618-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):c.8439C>T(p.Ser2813=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00801 in 1,610,454 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0083 (59 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.112

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 16-2103618-G-A is Benign according to our data. Variant chr16-2103618-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2103618-G-A is described in Lovd as [Benign]. Variant chr16-2103618-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.112 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00499 (760/152310) while in subpopulation NFE AF= 0.00863 (587/68028). AF 95% confidence interval is 0.00805. There are 4 homozygotes in gnomad4. There are 336 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 760 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8439C>T	p.Ser2813=	synonymous_variant	23/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8439C>T	p.Ser2813=	synonymous_variant	23/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00499 AC: 760 AN: 152192 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00863

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00481 AC: 1198 AN: 248816 Hom.: 11 AF XY: 0.00485 AC XY: 656 AN XY: 135294

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00231

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.00854

Gnomad OTH exome AF: 0.00527

GnomAD4 exome AF: 0.00833 AC: 12147 AN: 1458144 Hom.: 59 Cov.: 34 AF XY: 0.00815 AC XY: 5909 AN XY: 725386

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.00323

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00828

GnomAD4 genome AF: 0.00499 AC: 760 AN: 152310 Hom.: 4 Cov.: 31 AF XY: 0.00451 AC XY: 336 AN XY: 74464

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.00863

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00655 Hom.: 2

Bravo AF: 0.00496

EpiCase AF: 0.00889

EpiControl AF: 0.00753

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 03, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	PKD1: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2021	This variant is associated with the following publications: (PMID: 11216660, 11115377, 17574468, 18837007, 22383692, 24374109) -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 25, 2018

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1, p.Ser2813Ser variant was identified in 11 of 1112 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Afzal 2000, Garcia-Gonzalez 2007, Rossetti 2001, Rossetti 2012, Rossett 2001, Tan 2009). The variant was also identified in dbSNP (ID: rs117856830) 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 NHLBI GO Exome Sequencing Project in 71 of 8570 European American and in 3 of 4380 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 562 (1 homozygous) of 117700 chromosomes (freq. 0.005) in the following populations: European in 474 of 63998 chromosomes (freq. 0.007), Finnish in 26 of 6610 chromosomes (freq.0.004), Latino in 26 of 11522 chromosomes (freq. 0.002), South Asian in 17 of 16500 chromosomes (0.003), African in 12 of 9608 chromosomes (freq. 0.001), Other in 7 of 880 chromosomes (freq. 0.008), 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. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ser2813Ser 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, the variant is classified as a polymorphism by number of population and statistics studies (Afzal 2000, Garcia-Gonzalez 2007, Rossetti 2001, Rossetti 2012, Rossett 2001). 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	-0.42
Cadd	Benign	6.8
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs117856830; hg19: chr16-2153619;