rs2003782

Positions:

• chr16-2106446-G-A
• chr16-2106446-G-T

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.7441C>T​(p.Leu2481=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,588,648 control chromosomes in the GnomAD database, including 27,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6287 hom., cov: 33)
  • Exomes 𝑓: 0.16 (21307 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.199

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-2106446-G-A is Benign according to our data. Variant chr16-2106446-G-A is described in ClinVar as [Benign]. Clinvar id is 257001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2106446-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.199 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.7441C>T	p.Leu2481=	synonymous_variant	18/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.7441C>T	p.Leu2481=	synonymous_variant	18/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37139 AN: 152022 Hom.: 6264 Cov.: 33

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0906

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.237

GnomAD3 exomes AF: 0.155 AC: 27935 AN: 180552 Hom.: 3005 AF XY: 0.151 AC XY: 15137 AN XY: 99930

Gnomad AFR exome AF: 0.491

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.0911

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.161 AC: 231041 AN: 1436508 Hom.: 21307 Cov.: 33 AF XY: 0.158 AC XY: 113016 AN XY: 714054

Gnomad4 AFR exome AF: 0.487

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.240

Gnomad4 EAS exome AF: 0.000333

Gnomad4 SAS exome AF: 0.0923

Gnomad4 FIN exome AF: 0.182

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.245 AC: 37205 AN: 152140 Hom.: 6287 Cov.: 33 AF XY: 0.241 AC XY: 17909 AN XY: 74392

Gnomad4 AFR AF: 0.475

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0900

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.235

Alfa AF: 0.200 Hom.: 808

Bravo AF: 0.255

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 07, 2020

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The c.7441C>T, p.Leu2481Leu variant was identified in 21.44% of 8928 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

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

Sep 24, 2019

This variant is associated with the following publications: (PMID: 22608885) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2003782; hg19: chr16-2156447; COSMIC: COSV51919269; COSMIC: COSV51919269;