rs145850037

Positions:

• chr16-2103759-G-A
• chr16-2103759-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001009944.3(PKD1):​c.8298C>T​(p.Ser2766Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,609,970 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2766S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (9 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.730

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 16-2103759-G-A is Benign according to our data. Variant chr16-2103759-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2103759-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.73 with no splicing effect.
• BS2: High AC in GnomAd4 at 203 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.8298C>T	p.Ser2766Ser	synonymous_variant	23/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.8298C>T	p.Ser2766Ser	synonymous_variant	23/46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 203 AN: 151684 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.00100 AC: 248 AN: 247238 Hom.: 0 AF XY: 0.000957 AC XY: 129 AN XY: 134852

Gnomad AFR exome AF: 0.000973

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.00233 AC: 3397 AN: 1458168 Hom.: 9 Cov.: 34 AF XY: 0.00216 AC XY: 1566 AN XY: 725384

Gnomad4 AFR exome AF: 0.000689

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.00285

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00134 AC: 203 AN: 151802 Hom.: 0 Cov.: 31 AF XY: 0.00120 AC XY: 89 AN XY: 74180

Gnomad4 AFR AF: 0.000531

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00237

Gnomad4 OTH AF: 0.000952

Alfa AF: 0.000870 Hom.: 0

Bravo AF: 0.00153

EpiCase AF: 0.00164

EpiControl AF: 0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2021	This variant is associated with the following publications: (PMID: 12007219, 16430766, 17574468) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	PKD1: BS1, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 24, 2019

- -

Bile duct cancer Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Ser2766Ser variant was identified in 3 of 246 proband chromosomes (frequency: 0.012) from Japanese, Slovenian and American individuals or families with ADPKD, co-occurring with a pathogenic splicing PKD1 variant (c.8228-2delAG) in 1 Japanese individual (Garcia-Gonzalez 2007, Vouk 2006, Inoue 2002). The variant was also identified by our laboratory in an individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.2215C>T), increasing the likelihood that the p.Ser2766Ser variant does not have clinical significance. The variant was also identified in dbSNP (ID: rs145850037) as “NA”, and the ADPKD Mutation Database (classification likely neutral) and in the ClinVar database classified as Likely Benign by Prevention Genetics, but was not found in PKD1-LOVD, Clinvitae, GeneInsight COGR, MutDB and PKD1-LOVD 3.0. This variant was identified in the 1000 Genomes Project in 5 of 5000 chromosomes (frequency: 0.001), NHLBI GO Exome Sequencing Project in 21 of 8552 European American alleles (frequency: 0.0025) and in 5 of 4352 African American alleles (frequency: 0.0011), the Exome Aggregation Consortium database (August 8, 2016) in 118 of 115912 chromosomes (freq. 0.0010)) in the following populations: European (Non-Finnish) in 95 of 63278 chromosomes (freq. 0.0015), African in 11 of 8940 chromosomes (freq. 0.0012), Latino in 9 of 11392 chromosomes (freq. 0.00079), South Asian in 3 of 16460 chromosomes (freq. 00018), but was not seen in East Asian, Finnish, or Other populations; increasing the likelihood this could be a low frequency benign variant. The p.Ser2766Ser 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's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.8
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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: rs145850037; hg19: chr16-2153760;