16-2102128-A-G

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.9330T>C(p.Pro3110=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0677 in 1,536,054 control chromosomes in the GnomAD database, including 13,168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5904 hom., cov: 31)
  • Exomes 𝑓: 0.050 (7264 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.67

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=-1.01).
• BP6: Variant 16-2102128-A-G is Benign according to our data. Variant chr16-2102128-A-G is described in ClinVar as [Benign]. Clinvar id is 257042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2102128-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.9330T>C	p.Pro3110=	synonymous_variant	26/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.9330T>C	p.Pro3110=	synonymous_variant	26/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.235 AC: 34200 AN: 145742 Hom.: 5893 Cov.: 31

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.0865

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0612

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.226

GnomAD3 exomes AF: 0.0326 AC: 7348 AN: 225576 Hom.: 1268 AF XY: 0.0291 AC XY: 3599 AN XY: 123668

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.0274

Gnomad ASJ exome AF: 0.0374

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.0116

Gnomad FIN exome AF: 0.00557

Gnomad NFE exome AF: 0.0284

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0501 AC: 69691 AN: 1390220 Hom.: 7264 Cov.: 31 AF XY: 0.0509 AC XY: 35249 AN XY: 692220

Gnomad4 AFR exome AF: 0.238

Gnomad4 AMR exome AF: 0.0637

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0402

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.0408

Gnomad4 OTH exome AF: 0.0832

GnomAD4 genome AF: 0.235 AC: 34242 AN: 145834 Hom.: 5904 Cov.: 31 AF XY: 0.227 AC XY: 16163 AN XY: 71092

Gnomad4 AFR AF: 0.481

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0612

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.224

Alfa AF: 0.315 Hom.: 3897

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Pro3110Pro variant was identified as a polymorphism in 92 of 658 proband chromosomes (frequency: 0.140) from individuals or families with ADPKD (McCluskey 2002, Garcia-Gonzalez 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs144582212 “With unknown allele”, with a minor allele frequency of 0.1388 (695 of 5007 chromosomes in 1000 Genomes Project). The variant was not identified in the NHLBI Exome Sequencing Project (Exome Variant Server). This variant was identified in the Exome Aggregation Consortium (ExAC) database (March 14, 2016) in 20 of 69990 chromosomes (frequency: 0.0003) or 9 of 2566 African , 2 of 7098 Latino , 9 of 37172 European (Non-Finnish) chromosomes and was not found in populations of South Asians, East Asian, European (Finnish) and other. We cannot be certain that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was identified in Clinvitae by EmyClass and classified as benign. The variant was also identified in the PKD Mutation Database and classified as likely neutral. The p.Pro3110Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

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

Dec 19, 2019

This variant is associated with the following publications: (PMID: 24374109, 11857740, 22608885, 22383692, 22008521, 18837007, 17574468, 10854095) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.063
Dann	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs12926160; hg19: chr16-2152129; COSMIC: COSV51913910; COSMIC: COSV51913910;