16-2104490-C-T

Variant names:

• chr16-2104490-C-T
• rs199569003
• NM_001009944.3:c.8161+8G>A

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: -2.45
• 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 -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 Benign/Likely_benign. ClinVar VariationId is 257014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.8161+8G>A		splice_region_variant, intron_variant	Intron 22 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.8161+8G>A		splice_region_variant, intron_variant	Intron 22 of 45	1	NM_001009944.3	ENSP00000262304.4

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

GnomAD2 exomes AF: 0.00539 AC: 815 AN: 151340 AF XY: 0.00542

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 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

African (AFR) AF: 0.00109 AC: 33 AN: 30164

American (AMR) AF: 0.00382 AC: 140 AN: 36682

Ashkenazi Jewish (ASJ) AF: 0.00269 AC: 67 AN: 24922

East Asian (EAS) AF: 0.00 AC: 0 AN: 36780

South Asian (SAS) AF: 0.00451 AC: 358 AN: 79410

European-Finnish (FIN) AF: 0.0130 AC: 557 AN: 42782

Middle Eastern (MID) AF: 0.00273 AC: 11 AN: 4026

European-Non Finnish (NFE) AF: 0.00647 AC: 6809 AN: 1052816

Other (OTH) AF: 0.00433 AC: 246 AN: 56780

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

African (AFR) AF: 0.00110 AC: 43 AN: 39132

American (AMR) AF: 0.00600 AC: 90 AN: 15004

Ashkenazi Jewish (ASJ) AF: 0.00524 AC: 18 AN: 3436

East Asian (EAS) AF: 0.000204 AC: 1 AN: 4914

South Asian (SAS) AF: 0.00388 AC: 18 AN: 4642

European-Finnish (FIN) AF: 0.0173 AC: 180 AN: 10428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00661 AC: 444 AN: 67198

Other (OTH) AF: 0.00535 AC: 11 AN: 2056

Alfa AF: 0.00573 Hom.: 2

Bravo AF: 0.00442

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:2

Jan 29, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Apr 28, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD1 c.8161+8G>A alters a nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0054 in 151340 control chromosomes in the gnomAD database, including 5 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease phenotype. To our knowledge, no occurrence of c.8161+8G>A in individuals affected with PKD1-Biallelic Autosomal Recessive Polycystic Kidney Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 257014). Based on the evidence outlined above, the variant was classified as benign. -

Autosomal dominant polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BS2 -

PKD1-related disorder Benign:1

Aug 29, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs199569003; hg19: chr16-2154491;