rs9936029

Positions:

• chr16-2102653-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.8949-20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00596 in 1,610,648 control chromosomes in the GnomAD database, including 512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (276 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (236 hom.)
• Consequence: PKD1 NM_001009944.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.28

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-2102653-C-T is Benign according to our data. Variant chr16-2102653-C-T is described in ClinVar as [Benign]. Clinvar id is 257035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2102653-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.8949-20G>A		intron_variant		ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.8949-20G>A		intron_variant		1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4680 AN: 152204 Hom.: 274 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.00802 AC: 1978 AN: 246700 Hom.: 107 AF XY: 0.00585 AC XY: 788 AN XY: 134666

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.00640

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000497

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00336 AC: 4897 AN: 1458326 Hom.: 236 Cov.: 34 AF XY: 0.00285 AC XY: 2069 AN XY: 725480

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00711

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.0000384

Gnomad4 NFE exome AF: 0.000359

Gnomad4 OTH exome AF: 0.00779

GnomAD4 genome AF: 0.0308 AC: 4699 AN: 152322 Hom.: 276 Cov.: 33 AF XY: 0.0296 AC XY: 2207 AN XY: 74470

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0168 Hom.: 18

Bravo AF: 0.0347

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.32

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: rs9936029; hg19: chr16-2152654;