rs4018162

Variant names:

• chr16-2106937-C-G
• rs4018162
• NM_001009944.3:c.7077G>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001009944.3(PKD1):​c.7077G>C​(p.Arg2359Arg) 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:8
• Conservation: PhyloP100: 0.114
• Publications: 3 publications found

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]

MIR6511B1 (HGNC:50228): (microRNA 6511b-1) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -17 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 Benign/Likely_benign. ClinVar VariationId is 256996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.114 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 72 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.7077G>C	p.Arg2359Arg	synonymous_variant	Exon 17 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.7077G>C	p.Arg2359Arg	synonymous_variant	Exon 17 of 46	1	NM_001009944.3	ENSP00000262304.4

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

GnomAD2 exomes AF: 0.00446 AC: 1002 AN: 224708 AF XY: 0.00409

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0359 AC: 1102 AN: 30678

American (AMR) AF: 0.00240 AC: 107 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00292 AC: 76 AN: 26016

East Asian (EAS) AF: 0.00263 AC: 104 AN: 39616

South Asian (SAS) AF: 0.00443 AC: 380 AN: 85788

European-Finnish (FIN) AF: 0.0000265 AC: 1 AN: 37792

Middle Eastern (MID) AF: 0.00879 AC: 36 AN: 4094

European-Non Finnish (NFE) AF: 0.000292 AC: 322 AN: 1103988

Other (OTH) AF: 0.00341 AC: 203 AN: 59582

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0592 AC: 2383 AN: 40270

American (AMR) AF: 0.00689 AC: 105 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00733 AC: 38 AN: 5186

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68020

Other (OTH) AF: 0.0124 AC: 26 AN: 2098

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0104 Hom.: 8

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 06, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17574468) -

Sep 21, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:2

Apr 30, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Apr 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Oct 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs4018162; hg19: chr16-2156938;