rs2099534

Positions:

• chr16-2112838-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.3111A>G​(p.Leu1037=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0508 in 1,599,938 control chromosomes in the GnomAD database, including 2,591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (166 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2425 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.64

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 16-2112838-T-C is Benign according to our data. Variant chr16-2112838-T-C is described in ClinVar as [Benign]. Clinvar id is 256944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2112838-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.3111A>G	p.Leu1037=	synonymous_variant	13/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.3111A>G	p.Leu1037=	synonymous_variant	13/46	1	NM_001009944.3	P5
	ENST00000568795.1	n.161-209T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0379 AC: 5763 AN: 152194 Hom.: 166 Cov.: 33

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0398

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0432

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0587

Gnomad OTH AF: 0.0575

GnomAD3 exomes AF: 0.0378 AC: 9226 AN: 244380 Hom.: 236 AF XY: 0.0383 AC XY: 5099 AN XY: 133062

Gnomad AFR exome AF: 0.00938

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0331

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00591

Gnomad FIN exome AF: 0.0471

Gnomad NFE exome AF: 0.0579

Gnomad OTH exome AF: 0.0451

GnomAD4 exome AF: 0.0521 AC: 75491 AN: 1447626 Hom.: 2425 Cov.: 34 AF XY: 0.0508 AC XY: 36584 AN XY: 720570

Gnomad4 AFR exome AF: 0.00848

Gnomad4 AMR exome AF: 0.0316

Gnomad4 ASJ exome AF: 0.0348

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00578

Gnomad4 FIN exome AF: 0.0448

Gnomad4 NFE exome AF: 0.0607

Gnomad4 OTH exome AF: 0.0496

GnomAD4 genome AF: 0.0378 AC: 5761 AN: 152312 Hom.: 166 Cov.: 33 AF XY: 0.0364 AC XY: 2714 AN XY: 74490

Gnomad4 AFR AF: 0.0100

Gnomad4 AMR AF: 0.0397

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.0432

Gnomad4 NFE AF: 0.0588

Gnomad4 OTH AF: 0.0569

Alfa AF: 0.0438 Hom.: 31

Bravo AF: 0.0381

EpiCase AF: 0.0621

EpiControl AF: 0.0617

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
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+	-	- -

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 15, 2020	- -

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	clinical testing	GeneDx	Feb 13, 2020	This variant is associated with the following publications: (PMID: 10364515, 22383692, 15772804, 11857740, 17574468, 22008521, 18837007) -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.1
DANN	Benign	0.49

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: rs2099534; hg19: chr16-2162839; COSMIC: COSV51921280; COSMIC: COSV51921280;