chr16-2099737-G-A

Position:

chr16-2099737-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The ENST00000262304.9(PKD1):c.9957C>T(p.Ser3319=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,557,476 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 13 hom. )

Consequence

PKD1
ENST00000262304.9 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.734

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 16-2099737-G-A is Benign according to our data. Variant chr16-2099737-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2099737-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.734 with no splicing effect.

BS2

High AC in GnomAd4 at 557 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.9957C>T	p.Ser3319=	synonymous_variant	30/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.9957C>T	p.Ser3319=	synonymous_variant	30/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00366

AC:

557

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0155

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00442

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00341

AC:

489

AN:

143472

Hom.:

AF XY:

0.00328

AC XY:

253

AN XY:

77090

show subpopulations

Gnomad AFR exome

AF:

0.000876

Gnomad AMR exome

AF:

0.00224

Gnomad ASJ exome

AF:

0.00434

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000793

Gnomad FIN exome

AF:

0.0149

Gnomad NFE exome

AF:

0.00390

Gnomad OTH exome

AF:

0.00309

GnomAD4 exome

AF:

0.00371

AC:

5212

AN:

1405134

Hom.:

Cov.:

AF XY:

0.00359

AC XY:

2497

AN XY:

695876

show subpopulations

Gnomad4 AFR exome

AF:

0.000561

Gnomad4 AMR exome

AF:

0.00202

Gnomad4 ASJ exome

AF:

0.00387

Gnomad4 EAS exome

AF:

0.0000270

Gnomad4 SAS exome

AF:

0.000890

Gnomad4 FIN exome

AF:

0.0136

Gnomad4 NFE exome

AF:

0.00379

Gnomad4 OTH exome

AF:

0.00365

GnomAD4 genome

AF:

0.00366

AC:

557

AN:

152342

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

299

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000769

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0155

Gnomad4 NFE

AF:

0.00443

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00531

Hom.:

Bravo

AF:

0.00253

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PKD1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2021	This variant is associated with the following publications: (PMID: 22383692, 11967008) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 03, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ser3319Ser variant was identified in an NGS validation study and in a PHPLC validation study in 4 of 550 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD (Rossetti 2012, Rossetti 2002). The variant was also identified in dbSNP (ID: rs141101590) classified as â€šÃ„ÃºNAâ€šÃ„Ã¹. The variant was identified in the PKD Mutation Database classified as "likely neutral". This variant was identified in the 1000 Genomes Project in 10 of 5000 chromosomes (frequency: 0.002); HAPMAP-EUR in 5 of 1006 chromosomes (frequency: 0.005); HAPMAP-AMR in 5 of 694 chromosomes (frequency: 0.007); NHLBI GO Exome Sequencing Project (ESP) in 9 of 6278 (frequency 0.0014) in European American alleles and in 10 of 5000 (frequency 0.0006) African American alleles; and in the Exome Aggregation Consortium (ExAC) database (March 14, 20165) in 41 of 14290 alleles (frequency 0.003) increasing the likelihood this could be a low frequency benign variant. The variant was not identified in Clinvitae, ClinVar, COGR GeneInsight, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. The p.Ser3319Ser 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 likely 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.24

DANN

Benign

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over