rs80111665

chr16-2109320-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (57 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.46

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 -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 [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. This position pass quality control queck.
• BS2: High AC in GnomAd at 622 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.5847C>T	p.Ser1949=	synonymous_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.5847C>T	p.Ser1949=	synonymous_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 622 AN: 152232 Hom.: 13 Cov.: 33

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.: 35 AF XY: 0.00588 AC XY: 745 AN XY: 126784

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.: 57 Cov.: 34 AF XY: 0.00236 AC XY: 1679 AN XY: 711902

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.: 13 Cov.: 33 AF XY: 0.00497 AC XY: 370 AN XY: 74492

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.: 0

Bravo AF: 0.00372

Asia WGS AF: 0.0220 AC: 77 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2020	This variant is associated with the following publications: (PMID: 11012875, 22383692, 18837007, 22185115) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2018	- -

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

- -

PKD1-related condition Benign:1

Benign, criteria provided, single submitter

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). -

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 “With Likely benign allele”, 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. -

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

Other links and lift over

dbSNP: rs80111665; hg19: chr16-2159321;