rs145176597

Positions:

• chr16-2103693-C-T

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.8364G>A​(p.Ser2788=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,609,960 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.74

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=-0.75).
• BP6: Variant 16-2103693-C-T is Benign according to our data. Variant chr16-2103693-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2103693-C-T is described in Lovd as [Benign]. Variant chr16-2103693-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.74 with no splicing effect.
• BS2: High AC in GnomAd4 at 197 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.8364G>A	p.Ser2788=	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.8364G>A	p.Ser2788=	synonymous_variant	23/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 197 AN: 152028 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00111 AC: 269 AN: 243276 Hom.: 1 AF XY: 0.00117 AC XY: 156 AN XY: 133366

Gnomad AFR exome AF: 0.000349

Gnomad AMR exome AF: 0.000669

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.000786

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.00214 AC: 3127 AN: 1457814 Hom.: 5 Cov.: 34 AF XY: 0.00206 AC XY: 1493 AN XY: 725214

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000859

Gnomad4 FIN exome AF: 0.0000577

Gnomad4 NFE exome AF: 0.00258

Gnomad4 OTH exome AF: 0.00218

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152146 Hom.: 0 Cov.: 31 AF XY: 0.00102 AC XY: 76 AN XY: 74366

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000392

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00232

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00179 Hom.: 0

Bravo AF: 0.00138

EpiCase AF: 0.00267

EpiControl AF: 0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 13, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	PKD1: BP4, BP7, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 08, 2019

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Ser2788= variant was identified in 1 of 460 proband chromosomes (freq 0.002) from individuals or families with PKD (Rossetti 2012). The variant was also identified in dbSNP (ID: rs145176597) as “With Likely benign allele”, in Clinvitae and ClinVar (as likely benign by PreventionGenetics), ADPKD Mutation Database (as likely neutral), and PKD1-LOVD 3.0 (2x, unclassified with the probability of no functional affect), the 1000 Genomes Project in 4 of 5008 chromosomes (freq 0.0008), the NHLBI GO Exome Sequencing Project in 20 of 8446 European American alleles (freq 0.0023) and 2 in 4306 African American alleles (freq 0.00045), the genome Aggregation Database (beta, October 19th 2016) in 286 (1 homozygous) of 271612 chromosomes (freq. 0.001), the Exome Aggregation Consortium database (August 8th 2016) in 108 (1 homozygous) of 113342 chromosomes (freq. 0.001) in the following populations: European in 84 of 61652 chromosomes (freq. 0.001), South Asian in 13 of 16422 chromosomes (freq. 0.0008), Latino in 8 of 11282 chromosomes (freq. 0.0007), African in 2 of 8270 chromosomes (freq. 0.00024), and East Asian in 1 of 8378 chromosomes (freq. 0.0001), but was not seen in Finnish and other 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. This variant was not identified in GeneInsight-COGR, MutDB, and PKD1-LOVD databases. The p.Ser2788= 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 1 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 summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.4
DANN	Benign	0.94

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: rs145176597; hg19: chr16-2153694;