rs755496450

Positions:

• chr16-2089948-G-A
• chr16-2089948-G-C
• chr16-2089948-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000262304.9(PKD1):​c.12691C>T​(p.Gln4231Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: PKD1 ENST00000262304.9 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.04

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2089948-G-A is Pathogenic according to our data. Variant chr16-2089948-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2089948-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.12691C>T	p.Gln4231Ter	stop_gained	46/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.12691C>T	p.Gln4231Ter	stop_gained	46/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.12688C>T	p.Gln4230Ter	stop_gained	46/46	1		ENSP00000399501	A2
PKD1	ENST00000472577.1	n.719C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1_Strong+PS4_Moderate+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 1 (MIM#173900). (I) 0107 - 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). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is predicted to truncate part of the coiled-coil region (DECIPHER). (I) 0701 - Other protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, PMID: 32398770, PMID: 22508176). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with autosomal dominant polycystic kidney disease (ClinVar, PMIDs: 33168999, 19686598, 22508176, 29529603, 32398770, 27499327, 33532864). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000562326 / PMID: 19686598). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 27, 2017	- -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	49
DANN	Uncertain	0.99
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	D;D
Vest4		0.66
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs755496450; hg19: chr16-2139949;