rs1555453872

Positions:

• chr16-2107947-ACGCCAGC-A
• chr16-2107947-ACGCCAGC-ACGCCAGCCGCCAGC

Variant summary

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

The ENST00000262304.9(PKD1):​c.6994_7000del​(p.Ala2332TrpfsTer7) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 ENST00000262304.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.36

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 16-2107947-ACGCCAGC-A is Pathogenic according to our data. Variant chr16-2107947-ACGCCAGC-A is described in ClinVar as [Pathogenic]. Clinvar id is 972870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2107947-ACGCCAGC-A is described in Lovd as [Pathogenic]. Variant chr16-2107947-ACGCCAGC-A is described in Lovd as [Pathogenic]. Variant chr16-2107947-ACGCCAGC-A is described in Lovd as [Pathogenic]. Variant chr16-2107947-ACGCCAGC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.6994_7000del	p.Ala2332TrpfsTer7	frameshift_variant	16/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.6994_7000del	p.Ala2332TrpfsTer7	frameshift_variant	16/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.17e-7 AC: 1 AN: 1394114 Hom.: 0 AF XY: 0.00000145 AC XY: 1 AN XY: 687768

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: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2024	Frameshift 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: 32823016, 11012875, 31740684, 29633482, 22508176, 33437033, 11115377) -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 05, 2021	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. -

Polycystic kidney disease, adult type Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	Jul 19, 2024	PM2_Supporting+PVS1+PS4_Supporting+PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 09, 2022	- -

PKD1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The PKD1 c.6994_7000del7 variant is predicted to result in a frameshift and premature protein termination (p.Ala2332Trpfs*7). This variant has been reported to be pathogenic for autosomal dominant polycystic kidney disease (ADPKD) (see for example, Phakdeekitcharoen et al. 2000. PubMed ID: 11012875; Table S3 of Mallawaarachchi et al. 2021. PubMed ID: 33437033). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PKD1 are expected to be pathogenic. This variant is interpreted 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: rs1555453872; hg19: chr16-2157948;