rs199569003

chr16-2104490-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):c.8161+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,512,366 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (8 hom., cov: 20)
  • Exomes 𝑓: 0.0060 (58 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005573
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.45

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-2104490-C-T is Benign according to our data. Variant chr16-2104490-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2104490-C-T is described in Lovd as [Benign]. Variant chr16-2104490-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00547 (810/148004) while in subpopulation NFE AF= 0.00661 (444/67198). AF 95% confidence interval is 0.0061. There are 8 homozygotes in gnomad4. There are 400 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High AC in GnomAd at 810 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8161+8G>A		splice_region_variant, intron_variant		ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8161+8G>A		splice_region_variant, intron_variant		1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 810 AN: 147892 Hom.: 8 Cov.: 20

Gnomad AFR AF: 0.00110

Gnomad AMI AF: 0.00553

Gnomad AMR AF: 0.00601

Gnomad ASJ AF: 0.00524

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.00387

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00661

Gnomad OTH AF: 0.00541

GnomAD3 exomes AF: 0.00539 AC: 815 AN: 151340 Hom.: 5 AF XY: 0.00542 AC XY: 445 AN XY: 82048

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00348

Gnomad ASJ exome AF: 0.00335

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00382

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.00706

Gnomad OTH exome AF: 0.00551

GnomAD4 exome AF: 0.00603 AC: 8221 AN: 1364362 Hom.: 58 Cov.: 28 AF XY: 0.00593 AC XY: 4005 AN XY: 675900

Gnomad4 AFR exome AF: 0.00109

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.00269

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00451

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.00647

Gnomad4 OTH exome AF: 0.00433

GnomAD4 genome AF: 0.00547 AC: 810 AN: 148004 Hom.: 8 Cov.: 20 AF XY: 0.00554 AC XY: 400 AN XY: 72202

Gnomad4 AFR AF: 0.00110

Gnomad4 AMR AF: 0.00600

Gnomad4 ASJ AF: 0.00524

Gnomad4 EAS AF: 0.000204

Gnomad4 SAS AF: 0.00388

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.00661

Gnomad4 OTH AF: 0.00535

Alfa AF: 0.00573 Hom.: 2

Bravo AF: 0.00442

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 29, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 21, 2021	- -

Autosomal dominant polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 c.8161+8G>A variant was identified in 3 of 550 proband chromosomes (frequency: 0.005) from individuals or families with ADPKD (Rossetti 2002, Rossetti 2012). The variant was also identified in dbSNP (ID: rs199569003) as “NA”. In 1000 Genomes Project the variant is identified in 13 of 5000 chromosomes (frequency: 0.0026); in NHLBI GO Exome Sequencing Project in 46 of 7726 European American (frequency: 0.006) and in 4 of 3742 African American alleles (frequency: 0.001). The variant was identified in the Exome Aggregation Consortium database (March 2016) in 133 (4 homozygous) of 18570 chromosomes (freq. 0.007) in the following populations: Finnish in 5 of 120 chromosomes (freq. 0.04), other in 4 of 168 chromosomes (freq. 0.02), European (Non-Finnish) in 74 of 7230 chromosomes (freq. 0.01), Latino in 6 of 660 chromosomes (freq. 0.009), African in 6 of 1220 chromosomes (freq. 0.005) and South Asian in 38 of 8060 chromosomes (freq. 0.005), but was not seen in the East Asian population, increasing the likelihood this could be a low frequency benign variant. The variant is also identified in GeneInsight COGR (classified as benign) and in ADPKD database 4x as likely neutral. The c.8161+8G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. 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's criteria to be classified as benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

PKD1: BP4, BS2 -

PKD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 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	-0.89
Cadd	Benign	3.0
Dann	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.030
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: rs199569003; hg19: chr16-2154491;