rs1555445771

Positions:

• chr16-2091908-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Moderate

The NM_001009944.3(PKD1):​c.11412-2A>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000000685 in 1,459,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PKD1 NM_001009944.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.64

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 10 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.006351626 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.7, offset of 36, new splice context is: tcctgtgccgtgtatgacAGcgg. Cryptic site results in inframe 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-2091908-T-G is Pathogenic according to our data. Variant chr16-2091908-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 447951.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.11412-2A>C		splice_acceptor_variant		ENST00000262304.9
PKD1-AS1	NR_135175.1	n.179+294T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.11412-2A>C		splice_acceptor_variant		1	NM_001009944.3	P5
PKD1-AS1	ENST00000563284.3	n.70+300T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459364 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726010

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 23, 2017	- -

Polycystic kidney disease, adult type Pathogenic:1

Pathogenic, no assertion criteria provided

research

Genomics And Bioinformatics Analysis Resource, Columbia University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.95		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555445771; hg19: chr16-2141909;