rs776302294

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.588C>T(p.Ser196Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,221,104 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 11 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.88

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 -16 ACMG points.

BP6

Variant 16-2118404-G-A is Benign according to our data. Variant chr16-2118404-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2118404-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00116 (176/152172) while in subpopulation AMR AF= 0.00105 (16/15286). AF 95% confidence interval is 0.000665. There are 1 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 176 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.588C>T	p.Ser196Ser	synonymous_variant	Exon 5 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.588C>T	p.Ser196Ser	synonymous_variant	Exon 5 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1
PKD1	ENST00000423118.5 link	c.588C>T	p.Ser196Ser	synonymous_variant	Exon 5 of 46	1		ENSP00000399501.1		P98161-3

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

176

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000839

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00250

AC:

335

AN:

134196

Hom.:

AF XY:

0.00226

AC XY:

165

AN XY:

73054

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000778

Gnomad ASJ exome

AF:

0.0264

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000842

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00129

Gnomad OTH exome

AF:

0.00341

GnomAD4 exome

AF:

0.00124

AC:

1321

AN:

1068932

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

664

AN XY:

540998

show subpopulations

Gnomad4 AFR exome

AF:

0.000314

Gnomad4 AMR exome

AF:

0.000703

Gnomad4 ASJ exome

AF:

0.0258

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000857

Gnomad4 FIN exome

AF:

0.0000298

Gnomad4 NFE exome

AF:

0.000565

Gnomad4 OTH exome

AF:

0.00288

GnomAD4 genome

AF:

0.00116

AC:

176

AN:

152172

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.0242

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000839

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00371

Hom.:

Bravo

AF:

0.00141

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 20, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 13, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Dec 14, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17574468) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polycystic kidney disease, adult type

Benign:1

Aug 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Ser196= variant was identified in 2 of 164 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs776302294) as "With other allele ", ClinVar (classified as benign by Athena Diagnostics; as likely benign by PreventionGenetics and ARUP), and in ADPKD Mutation Database (likely neutral). The variant was not identified in LOVD 3.0, or PKD1-LOVD, databases. The variant was identified in control databases in 342 of 159848 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 14724 chromosomes (freq: 0.00007), Other in 14 of 4544 chromosomes (freq: 0.003), Latino in 18 of 24560 chromosomes (freq: 0.0007), European in 78 of 64948 chromosomes (freq: 0.001), Ashkenazi Jewish in 212 of 8190 chromosomes (freq: 0.03), and South Asian in 19 of 22622 chromosomes (freq: 0.0008), while the variant was not observed in the East Asian, and Finnish, populations. 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 p.Ser196= 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) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.40

Position offset: -8

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