rs1555444985

Positions:

• chr16-2090781-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001009944.3(PKD1):​c.12031C>T​(p.Gln4011Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,460,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PKD1 NM_001009944.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.84

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2090781-G-A is Pathogenic according to our data. Variant chr16-2090781-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 447961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2090781-G-A is described in Lovd as [Pathogenic]. Variant chr16-2090781-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.12031C>T	p.Gln4011Ter	stop_gained	44/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.12031C>T	p.Gln4011Ter	stop_gained	44/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.12028C>T	p.Gln4010Ter	stop_gained	44/46	1		ENSP00000399501	A2
PKD1	ENST00000472577.1	n.59C>T		non_coding_transcript_exon_variant	1/3	2
PKD1	ENST00000564313.1	n.552C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460256 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726436

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12220456, 9521593, 30650191, 33639313, 10729710, 10923038, 22508176, 35783601, 34032358, 25333066, 22383692) -

Polycystic kidney disease Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Gln4011* variant was identified in 6 of 2598 proband chromosomes (frequency: 0.002) from individuals or families with autosomal dominant polycystic kidney disease and was not identified in 518 control chromosomes from healthy individuals (Hwang 2016, Rossetti 2012, Eo 2002, Bogdanova 2000, Audrézet 2012, Daniells 1998, Kim 2000, Stekrova 2009). The variant was also identified in ClinVar (classified as pathogenic by Athena Diagnostics and Fulgent Genetics) and in the ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in LOVD 3.0 or the PKD1-LOVD databases. It was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Gln4011* variant leads to a premature stop codon at position 4011, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD1 gene are an established mechanism of disease in autosomal dominant polycystic kidney disease and is the type of variant expected to cause the disorder. 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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	57
DANN	Uncertain	0.99
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.73	D
MutationTaster	Benign	1.0	A;A
Vest4		0.84
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555444985; hg19: chr16-2140782;