rs9935526

Positions:

• chr16-2109995-G-A

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.5172C>T​(p.Ala1724=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,609,216 control chromosomes in the GnomAD database, including 29,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6284 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22756 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.914

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=-0.89).
• BP6: Variant 16-2109995-G-A is Benign according to our data. Variant chr16-2109995-G-A is described in ClinVar as [Benign]. Clinvar id is 256974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109995-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.914 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.5172C>T	p.Ala1724=	synonymous_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.5172C>T	p.Ala1724=	synonymous_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37417 AN: 152074 Hom.: 6269 Cov.: 33

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0867

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.241

GnomAD3 exomes AF: 0.161 AC: 38922 AN: 242448 Hom.: 4386 AF XY: 0.155 AC XY: 20550 AN XY: 132508

Gnomad AFR exome AF: 0.486

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.232

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0873

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.165 AC: 240747 AN: 1457024 Hom.: 22756 Cov.: 35 AF XY: 0.163 AC XY: 117821 AN XY: 724784

Gnomad4 AFR exome AF: 0.484

Gnomad4 AMR exome AF: 0.119

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0896

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.246 AC: 37477 AN: 152192 Hom.: 6284 Cov.: 33 AF XY: 0.241 AC XY: 17950 AN XY: 74402

Gnomad4 AFR AF: 0.471

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.235

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0863

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.238

Alfa AF: 0.196 Hom.: 1162

Bravo AF: 0.257

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.5172C>T, p.Ala1724Ala variant was identified in 17% of 18662 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, 10364515) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.10
DANN	Benign	0.74

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: rs9935526; hg19: chr16-2159996; COSMIC: COSV51920023; COSMIC: COSV51920023;