chr16-2093916-GACAGCC-G

Position:

• chr16-2093916-GACAGCC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM4 PP5_Very_Strong

The NM_001009944.3(PKD1):​c.10710_10715del​(p.Ala3571_Val3572del) variant causes a 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 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.46

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

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity PKD1_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) 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 id is 434001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2093916-GACAGCC-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.10710_10715del	p.Ala3571_Val3572del	inframe_deletion	36/46	ENST00000262304.9	NP_001009944.3
PKD1-AS1	NR_135175.1	n.304-790_304-785del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.10710_10715del	p.Ala3571_Val3572del	inframe_deletion	36/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1-AS1	ENST00000563284.3	n.195-790_195-785del		intron_variant, non_coding_transcript_variant		3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.0000480

Gnomad4 NFE exome AF: 0.00000545

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2018	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 21, 2022	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2023	In-frame deletion of 2 amino acids in a non-repeat region; Not observed 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) -

Autosomal dominant polycystic kidney disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs777460677; hg19: chr16-2143917;