chr16-2093916-GACAGCC-G

Variant names:

• chr16-2093916-GACAGCC-G
• rs777460677
• NM_001009944.3:c.10710_10715delGGCTGT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM4 PP5_Very_Strong

The NM_001009944.3(PKD1):​c.10710_10715delGGCTGT​(p.Ala3571_Val3572del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000699 in 1,430,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: PKD1 NM_001009944.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.46
• Publications: 1 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]

PKD1-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001009944.3
• PM4: Nonframeshift variant in NON repetitive region in NM_001009944.3.
• PP5: Variant 16-2093916-GACAGCC-G is Pathogenic according to our data. Variant chr16-2093916-GACAGCC-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 434001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.10710_10715delGGCTGT	p.Ala3571_Val3572del	disruptive_inframe_deletion	Exon 36 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.10710_10715delGGCTGT	p.Ala3571_Val3572del	disruptive_inframe_deletion	Exon 36 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000699 AC: 10 AN: 1430312 Hom.: 0 AF XY: 0.00000845 AC XY: 6 AN XY: 709984

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

African (AFR) AF: 0.00 AC: 0 AN: 32924

American (AMR) AF: 0.0000238 AC: 1 AN: 42060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25738

East Asian (EAS) AF: 0.00 AC: 0 AN: 38448

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83242

European-Finnish (FIN) AF: 0.0000480 AC: 2 AN: 41644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000545 AC: 6 AN: 1101120

Other (OTH) AF: 0.00 AC: 0 AN: 59390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000571497), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:3

Feb 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 24, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKD1 c.10710_10715del; p.Ala3571_Val3572del variant (rs777460677) has been described in the literature in association with autosomal dominant polycystic kidney disease (ADPKD; Alberer 2010, Canaud 2010, He 2018). It is reported in ClinVar (Variation ID: 434001), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes 2 residues (alanine and valine), leaving the rest of the protein in-frame. Based on available information, this variant is considered likely pathogenic. REFERENCES Alberer M et al. Reduced methotrexate clearance and renal impairment in a boy with osteosarcoma and earlier undetected autosomal dominant polycystic kidney disease (ADPKD). J Pediatr Hematol Oncol. 2010 Nov;32(8):e314-6. Canaud G et al. Therapeutic mTOR inhibition in autosomal dominant polycystic kidney disease: What is the appropriate serum level? Am J Transplant. 2010 Jul;10(7):1701-6. He W et al. Novel mutations of PKD genes in Chinese patients suffering from autosomal dominant polycystic kidney disease and seeking assisted reproduction. BMC Med Genet. 2018 Oct 17;19(1):186.

Jun 25, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.001 for a dominant condition (v4: 10 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic/likely pathogenic by clinical laboratories in ClinVar, and reported in the literature in individuals with ADPKD (PMIDs: 20921908, 30989420, 23300259, 35778421; pkdb.mayo.edu). Evidence in support of benign classification: In-frame insertion/deletion fully contained in a repetitive region that has low conservation. Additional information: This variant is heterozygous; This gene is associated with autosomal dominant disease. Polycystic kidney disease 1 (MIM#173900) is predominantly caused by monoallelic variants, with rare reports of biallelic variants causing disease (OMIM); No published functional evidence has been identified for this variant; No comparable in-frame deletion variants have previous evidence for pathogenicity. However, a larger in-frame deletion affecting this repeat region has been classified as likely pathogenic by a clinical laboratory in ClinVar; Variant is not located in an established domain, motif, hotspot or informative constraint region; Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 1 (MIM#173900); Inheritance information for this variant is not currently available in this individual.

not provided Pathogenic:2

Apr 25, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 2 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20642692, 20921908, 30333007, 37509056)

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal dominant polycystic kidney disease Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Ala3571_Val3572del variant was identified by Cannaud (2010) in a kidney donor, whose kidneys were transplanted in two recipients. After transplantation, both patients developed severe transplant cystic disease. Donor DNA sequence identified a novel hypomorphic mutation in PKD1 (10710_10715del6) as the only likely mutation. This deletion is located in the fourth transmembrane (TM) region of polycystin-1 and is predicted to change the site of the TM domain. The p.Ala3571_Val3572del variant was not identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC version 0.3 released January 13, 2015), COSMIC, MutDB, the ClinVar, Clinvitae, GeneInsight COGR through the Canadian Open Genetics Repository (http://opengenetics.ca/) and in LOVD PKD1 and LOVD3.0 PKD1 Databases. The variant was identified in the Mayo Clinic PKD1 database and was classified as Likely Pathogenic. This variant is an in-frame deletion resulting in the removal of Ala residue at codon 3571 and Val residue at codon 3572 resulting in loss a critical domain region and potentially loss of function. This type of variant is expected to cause Autosomal Dominant Polycystic Kidney Disease, consistent with the clinical diagnosis in this individual. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=36/164	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs777460677; hg19: chr16-2143917;