rs2091431794

Variant names:

• chr16-2090284-C-T
• rs2091431794
• NM_001009944.3:c.12444+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001009944.3(PKD1):​c.12444+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: PKD1 NM_001009944.3 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.47
• 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]

MIR1225 (HGNC:33931): (microRNA 1225) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.023698885 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.5, offset of 4, new splice context is: tggGTacgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2090284-C-T is Pathogenic according to our data. Variant chr16-2090284-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 975069.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.12444+1G>A		splice_donor_variant, intron_variant	Intron 45 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.12444+1G>A		splice_donor_variant, intron_variant	Intron 45 of 45	1	NM_001009944.3	ENSP00000262304.4
PKD1	ENST00000423118.5	c.12441+1G>A		splice_donor_variant, intron_variant	Intron 45 of 45	1		ENSP00000399501.1
MIR1225	ENST00000408729.1	n.1G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
PKD1	ENST00000472577.1	n.472+1G>A		splice_donor_variant, intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Pathogenic:1

Mar 22, 2019

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous canonical splice-site variant, NM_001009944.2(PKD1):c.12444+1G>A, has been identified in Intron 45 of 45 of the PKD1 gene. The nucleotide at this position has very high conservation (Phylop UCSC). This nucleotide substitution is predicted to cause aberrant splicing of the last exon in the PKD1 gene (Human splicing Finder, NetGene2, Fruit fly). This variant is predicted to result in loss of protein function through truncation (RT-PCR confirms it affects splicing and causes p.(Phe4149Metfs*8) (Yu, C. et al (2014)), which is a reported mechanism of pathogenicity for this gene. The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic and segregated with disease in one family with autosomal dominant polycystic kidney disease (Yu, C. et al (2014)). Other frameshift variants in the same region have also been shown to cause polycystic kidney disease (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

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 PKD1 c.12444+1G>A variant not identified in the dbSNP, ClinVar, ADPKD Mutation Database, or PKD1-LOVD databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant was identified in the literature as pathogenic (Abdelwahed_2018_29860066, Yu_2014_24575920). In addition, functional studies by RT-PCR using primers located in exon-exon junctional region of the cDNA found that c.12444 + 1G>A definitely destroyed the native splice site and created a novel donor site with truncating effect (Yu_2014_24575920). It was also reported the variant was found to segregate with disease in three family members (Yu_2014_24575920). The c.12444+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence; 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Autosomal dominant polycystic kidney disease Pathogenic:1

Dec 06, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in PKD1 occurs within the canonical splice acceptor site of intron 45. It is observed to cause cryptic donor site activation in RNA assays, resulting in an in-frame deletion (removes amino acids 4149-4304) that is expected to escape nonsense-mediated decay and remove <10% of the protein including the coiled coil domain which is a critical functional domain for PKD1 (PMID: 24575920, 9192675, 25574838). This variant is absent from the population database gnomAD v4.1. This variant has been reported in at least two unrelated families with autosomal dominant polycystic kidney disease and segregates with disease in multiple affected individuals in one family (PMID: 24575920, 32939031). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Moderate, PS4_Moderate, PM2_Supporting -

not provided Pathogenic:1

Jan 12, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.5
GERP RS		4.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.72		Position offset: -3
DS_DL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs2091431794; hg19: chr16-2140285;