rs116114803

chr16-2093864-G-Achr16-2093864-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):c.10768C>T(p.Leu3590=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 1,569,998 control chromosomes in the GnomAD database, including 941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (63 hom., cov: 33)
  • Exomes 𝑓: 0.032 (878 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.335

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-2093864-G-A is Benign according to our data. Variant chr16-2093864-G-A is described in ClinVar as [Benign]. Clinvar id is 256894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2093864-G-A is described in Lovd as [Benign]. Variant chr16-2093864-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.335 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0231 (3514/152294) while in subpopulation NFE AF= 0.0379 (2577/68000). AF 95% confidence interval is 0.0367. There are 63 homozygotes in gnomad4. There are 1656 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3512 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.10768C>T	p.Leu3590=	synonymous_variant	36/46	ENST00000262304.9
PKD1-AS1	NR_135175.1	n.303+852G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.10768C>T	p.Leu3590=	synonymous_variant	36/46	1	NM_001009944.3	P5
PKD1-AS1	ENST00000563284.3	n.194+852G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3512 AN: 152176 Hom.: 63 Cov.: 33

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0296

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0220 AC: 4115 AN: 187406 Hom.: 59 AF XY: 0.0223 AC XY: 2276 AN XY: 102174

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.00782

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0111

Gnomad FIN exome AF: 0.0371

Gnomad NFE exome AF: 0.0350

Gnomad OTH exome AF: 0.0233

GnomAD4 exome AF: 0.0324 AC: 45921 AN: 1417704 Hom.: 878 Cov.: 33 AF XY: 0.0319 AC XY: 22428 AN XY: 703030

Gnomad4 AFR exome AF: 0.00498

Gnomad4 AMR exome AF: 0.00834

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.0000532

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.0348

Gnomad4 NFE exome AF: 0.0376

Gnomad4 OTH exome AF: 0.0258

GnomAD4 genome AF: 0.0231 AC: 3514 AN: 152294 Hom.: 63 Cov.: 33 AF XY: 0.0222 AC XY: 1656 AN XY: 74462

Gnomad4 AFR AF: 0.00630

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.0296

Gnomad4 NFE AF: 0.0379

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0241 Hom.: 24

Bravo AF: 0.0210

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 08, 2020	- -

Autosomal dominant polycystic kidney disease Benign:1

Benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2020

This variant is associated with the following publications: (PMID: 19686598, 11058904, 15772804) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	6.8
Dann	Benign	0.72
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs116114803; hg19: chr16-2143865;