rs141101590

Variant names:

• chr16-2099737-G-A
• rs141101590
• NM_001009944.3:c.9957C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.9957C>T​(p.Ser3319Ser) 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 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.734
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 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 Benign/Likely_benign. ClinVar VariationId is 257047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.734 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00366 (557/152342) while in subpopulation NFE AF = 0.00443 (301/68022). AF 95% confidence interval is 0.00401. There are 1 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.9957C>T	p.Ser3319Ser	synonymous_variant	Exon 30 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.9957C>T	p.Ser3319Ser	synonymous_variant	Exon 30 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00366 AC: 557 AN: 152224 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.00341 AC: 489 AN: 143472 AF XY: 0.00328

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 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.: 13 Cov.: 27 AF XY: 0.00359 AC XY: 2497 AN XY: 695876

African (AFR) AF: 0.000561 AC: 18 AN: 32070

American (AMR) AF: 0.00202 AC: 77 AN: 38048

Ashkenazi Jewish (ASJ) AF: 0.00387 AC: 98 AN: 25350

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 36976

South Asian (SAS) AF: 0.000890 AC: 72 AN: 80922

European-Finnish (FIN) AF: 0.0136 AC: 620 AN: 45554

Middle Eastern (MID) AF: 0.000736 AC: 3 AN: 4076

European-Non Finnish (NFE) AF: 0.00379 AC: 4110 AN: 1083802

Other (OTH) AF: 0.00365 AC: 213 AN: 58336

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00401 AC XY: 299 AN XY: 74490

African (AFR) AF: 0.000769 AC: 32 AN: 41588

American (AMR) AF: 0.00216 AC: 33 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0155 AC: 165 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00443 AC: 301 AN: 68022

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00531 Hom.: 0

Bravo AF: 0.00253

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 25, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22383692, 11967008) -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BP7 -

Polycystic kidney disease, adult type Benign:2

May 03, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: 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.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 “NA”. 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

Jan 01, 2019

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.24
DANN	Benign	0.70
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs141101590; hg19: chr16-2149738; COSMIC: COSV99238415; COSMIC: COSV99238415;