rs141101590

chr16-2099737-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001009944.3(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 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.734

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 -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 GnomAd at 557 AD gene.

Transcripts

RefSeq

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

Ensembl

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

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

GnomAD3 exomes AF: 0.00341 AC: 489 AN: 143472 Hom.: 2 AF XY: 0.00328 AC XY: 253 AN XY: 77090

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

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.: 1 Cov.: 32 AF XY: 0.00401 AC XY: 299 AN XY: 74490

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.: 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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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

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Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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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

Benign, criteria provided, single submitter

research

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

Jan 01, 2019

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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

Other links and lift over

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