rs4018162

Positions:

• chr16-2106937-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.7077G>C​(p.Arg2359=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,583,042 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (72 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (43 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.114

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 16-2106937-C-G is Benign according to our data. Variant chr16-2106937-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 256996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2106937-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.114 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.7077G>C	p.Arg2359=	synonymous_variant	17/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.7077G>C	p.Arg2359=	synonymous_variant	17/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2629 AN: 150838 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00690

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00731

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.00446 AC: 1002 AN: 224708 Hom.: 22 AF XY: 0.00409 AC XY: 511 AN XY: 124862

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.00330

Gnomad EAS exome AF: 0.00487

Gnomad SAS exome AF: 0.00537

Gnomad FIN exome AF: 0.0000949

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.00422

GnomAD4 exome AF: 0.00163 AC: 2331 AN: 1432094 Hom.: 43 Cov.: 29 AF XY: 0.00170 AC XY: 1213 AN XY: 713516

Gnomad4 AFR exome AF: 0.0359

Gnomad4 AMR exome AF: 0.00240

Gnomad4 ASJ exome AF: 0.00292

Gnomad4 EAS exome AF: 0.00263

Gnomad4 SAS exome AF: 0.00443

Gnomad4 FIN exome AF: 0.0000265

Gnomad4 NFE exome AF: 0.000292

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.0175 AC: 2635 AN: 150948 Hom.: 72 Cov.: 32 AF XY: 0.0173 AC XY: 1275 AN XY: 73870

Gnomad4 AFR AF: 0.0592

Gnomad4 AMR AF: 0.00689

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00733

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.0124

Alfa AF: 0.0104 Hom.: 8

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	This variant is associated with the following publications: (PMID: 17574468) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 30, 2022	- -

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.Arg2359= variant was identified in 3 of 164 proband chromosomes (frequency: 0.018) from individuals or families with ADPKD and was not identified in 342 control chromosomes from healthy individuals (Garcia-Gonzalez, 2007). The variant was also identified in dbSNP (ID: rs4018162) as “With Benign allele”, Clinvitae and ClinVar (as benign by PreventionGenetics) and ADPKD Mutation Database (as likely benign). This variant was identified in the 1000 Genomes Project in 106 of 5008 chromosomes (frequency: 0.021), the genome Aggregation Database (beta, October 19th 2016) in 950 (19 homozygous) of 222394 chromosomes (freq. 0.0042), the Exome Aggregation Consortium database (August 8th 2016) in 253 of 85618 chromosomes (freq. 0.003) in the following populations: African in 91 of 4854 chromosomes (freq. 0.018), South Asian in 84 of 13972 chromosomes (freq. 0.006), East Asian in 25 of 6664 chromosomes (freq. 0.0037), Latino in 22 of 8658 chromosomes (freq. 0.0025), European in 30 of 47220 chromosomes (freq. 0.0006), and Finnish in 1 of 3634 chromosomes (freq. 0.000275), but was not seen in 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. In addition the variant was identified with a co-occurring pathogenic PKD1 variant (c.7863+1delG) by our laboratory in a patient with ADPKD, increasing the likelihood that the p.Arg2359= variant does not have clinical significance. This variant was not identified in GeneInsight COGR, MutDB, PKD1-LOVD, PKD1-LOVD 3.0, and the NHLBI GO Exome Sequencing Project databases. The p.Arg2359= 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 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. -

PKD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.8
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs4018162; hg19: chr16-2156938;