rs150949575

chr16-2099989-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001009944.3(PKD1):c.9795C>T(p.Ser3265=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,564,930 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (6 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.306

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 16-2099989-G-A is Benign according to our data. Variant chr16-2099989-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 586309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2099989-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.306 with no splicing effect.
• BS2: High AC in GnomAd at 358 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.9795C>T	p.Ser3265=	synonymous_variant	29/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.9795C>T	p.Ser3265=	synonymous_variant	29/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00164 AC: 276 AN: 168488 Hom.: 0 AF XY: 0.00159 AC XY: 143 AN XY: 89986

Gnomad AFR exome AF: 0.000223

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000115

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.00236

GnomAD4 exome AF: 0.00234 AC: 3308 AN: 1412568 Hom.: 6 Cov.: 32 AF XY: 0.00229 AC XY: 1599 AN XY: 698584

Gnomad4 AFR exome AF: 0.000373

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.000307

Gnomad4 NFE exome AF: 0.00276

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00235 AC: 358 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.00205 AC XY: 153 AN XY: 74500

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00594

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00307

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00210 Hom.: 0

Bravo AF: 0.00283

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	PKD1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2019	This variant is associated with the following publications: (PMID: 22383692, 17574468) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 09, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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, 2019

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Ser3265= variant was identified in 3 of 530 proband chromosomes (frequency: 0.006) from individuals or families with ADPKD, and was not identified in 342 control chromosomes from healthy individuals (Garcia-Gonzalez 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs150949575) as “NA”, ADPKD Mutation Database (likely neutral), the 1000 Genomes Project in 6 of 5008 chromosomes (frequency: 0.001) the NHLBI GO Exome Sequencing Project in 22 of 8382 European American alleles (freq: 0.003) and 2 in 4268 African American alleles (freq: 0.0005), the genome Aggregation Database (beta, October 19th 2016) in 295 of 192204 chromosomes (freq. 0.002), the Exome Aggregation Consortium database (August 8th 2016) in 31 of 22232 chromosomes (freq. 0.0014) in the following populations: Latino in 2 of 592 chromosomes (freq. 0.003), European in 28 of 8570 chromosomes (freq. 0.003) and African in 1 of 2192 chromosomes (freq. 0.0005), but was not seen in East Asian, Finnish, other and South Asian populations, increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. In addition the variant was identified with a co-occurring pathogenic PKD1 variant (p.Trp1243X) by our laboratory in a patient with ADPKD, increasing the likelihood that the p.Ser3265=variant does not have clinical significance. The variant was not identified in HAPMAP, GeneInsight COGR, ClinVar, Clinvitae, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. The p.Ser3265= 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 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	-0.69
Cadd	Benign	7.6
Dann	Benign	0.91

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: rs150949575; hg19: chr16-2149990;