rs80111665

Positions:

chr16-2109320-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001009944.3(PKD1):c.5847C>T(p.Ser1949=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,587,532 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 13 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 57 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.46

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 16-2109320-G-A is Benign according to our data. Variant chr16-2109320-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109320-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-3.46 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00408 (622/152350) while in subpopulation EAS AF= 0.0539 (279/5174). AF 95% confidence interval is 0.0487. There are 13 homozygotes in gnomad4. There are 370 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 622 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.5847C>T	p.Ser1949=	synonymous_variant	15/46	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.5847C>T	p.Ser1949=	synonymous_variant	15/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00409

AC:

622

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.0540

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00663

AC:

1518

AN:

228966

Hom.:

AF XY:

0.00588

AC XY:

745

AN XY:

126784

show subpopulations

Gnomad AFR exome

AF:

0.000213

Gnomad AMR exome

AF:

0.00329

Gnomad ASJ exome

AF:

0.00435

Gnomad EAS exome

AF:

0.0541

Gnomad SAS exome

AF:

0.00162

Gnomad FIN exome

AF:

0.0170

Gnomad NFE exome

AF:

0.000856

Gnomad OTH exome

AF:

0.00677

GnomAD4 exome

AF:

0.00242

AC:

3475

AN:

1435182

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

1679

AN XY:

711902

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.00413

Gnomad4 ASJ exome

AF:

0.00440

Gnomad4 EAS exome

AF:

0.0403

Gnomad4 SAS exome

AF:

0.00184

Gnomad4 FIN exome

AF:

0.0154

Gnomad4 NFE exome

AF:

0.000414

Gnomad4 OTH exome

AF:

0.00572

GnomAD4 genome

AF:

0.00408

AC:

622

AN:

152350

Hom.:

Cov.:

AF XY:

0.00497

AC XY:

370

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.0539

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.0150

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00190

Hom.:

Bravo

AF:

0.00372

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2020	This variant is associated with the following publications: (PMID: 11012875, 22383692, 18837007, 22185115) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 29, 2019

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ser1949= variant was identified in 1 of 460 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD, and was present in 1 of 92 control chromosomes (frequency: 0.01) from healthy individuals (Rossetti_2012_22383692, Phakdeekitcharoen_2000_11012875). The variant was also identified in dbSNP (ID: rs80111665) as â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, ClinVar (classified as benign by ARUP Laboratories and likely benign by PreventionGenetics), and the ADPKD Mutation Database (classified as likely neutral). The variant was not identified in GeneInsight-COGR, LOVD 3.0, or PKD1-LOVD databases. The variant was identified in control databases in 1665 of 257370 chromosomes (38 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 3 of 22624 chromosomes (freq: 0.0001), Other in 41 of 6190 chromosomes (freq: 0.007), Latino in 112 of 33994 chromosomes (freq: 0.003), European Non-Finnish in 123 of 119088 chromosomes (freq: 0.001), Ashkenazi Jewish in 53 of 9568 chromosomes (freq: 0.006), East Asian in 1005 of 18588 chromosomes (freq: 0.05), European Finnish in 280 of 17560 chromosomes (freq: 0.02), and South Asian in 48 of 29758 chromosomes (freq: 0.002). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Ser1949= 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 summary, based on the above information this variant meets our laboratory criteria to be classified as benign. -

PKD1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.32

DANN

Benign

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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