rs185355445

Variant names:

• chr16-2093096-G-A
• rs185355445
• NM_001009944.3:c.11017-3C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001009944.3(PKD1):​c.11017-3C>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00229 in 1,612,336 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (2 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, intron
• Scores: Splicing: ADA: 0.007748
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 6.97
• 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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 16-2093096-G-A is Benign according to our data. Variant chr16-2093096-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 440126.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00133 (203/152320) while in subpopulation NFE AF = 0.00245 (167/68028). AF 95% confidence interval is 0.00215. There are 0 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.11017-3C>T		splice_region_variant, intron_variant	Intron 37 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.11017-3C>T		splice_region_variant, intron_variant	Intron 37 of 45	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00106 AC: 264 AN: 248590 AF XY: 0.00101

Gnomad AFR exome AF: 0.000442

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.000824

GnomAD4 exome AF: 0.00239 AC: 3484 AN: 1460016 Hom.: 2 Cov.: 32 AF XY: 0.00231 AC XY: 1676 AN XY: 726292

African (AFR) AF: 0.000269 AC: 9 AN: 33470

American (AMR) AF: 0.000335 AC: 15 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.000615 AC: 32 AN: 52042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 0.00294 AC: 3267 AN: 1111868

Other (OTH) AF: 0.00267 AC: 161 AN: 60334

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.00119 AC XY: 89 AN XY: 74482

African (AFR) AF: 0.000577 AC: 24 AN: 41572

American (AMR) AF: 0.000392 AC: 6 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000470 AC: 5 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00245 AC: 167 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00165 Hom.: 0

Bravo AF: 0.00127

EpiCase AF: 0.00213

EpiControl AF: 0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polycystic kidney disease, adult type Uncertain:2

Jul 15, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4 -

Oct 04, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

not specified Uncertain:1

Jan 29, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

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 c.11017-3C>T variant was identified in 1 of 48 proband chromosomes (frequency: 0.02) from American individuals or families with ADPKD and no family history (Reed 2008). The variant was inherited from an unaffected parent however it was not identified in 150 control chromosomes from healthy individuals (Reed 2008). The variant was also identified in dbSNP (ID: rs185355445) as “NA”, the ADPKD Mutation Database (classification likely neutral), the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), HAPMAP-EUR in 1 of 1006 chromosomes (frequency: 0.001), NHLBI GO Exome Sequencing Project in 26 of 8598 European American alleles (frequency: 0.003) and in 2 of 4394 African American alleles (frequency: 0.0005), and in the Exome Aggregation Consortium database (August 8, 2016) in 119 of 118808 chromosomes (frequency: 0.001) in the following populations: European (Non-Finnish) in 110 of 64720 chromosomes (frequency: 0.002), Finnish in 3 of 6600 chromosomes (frequency: 0.0005), African in 3 of 9970 chromosomes (frequency: 0.0003), Latino in 3 of 11536 chromosomes (frequency: 0.0003), but was not seen in East Asian, South Asian, and Other populations. The variant was not identified in Clinvitae, ClinVar, GeneInsight-COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. The variant was identified by our laboratory in 1 individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.12178C>T, p.Gln4060X), increasing the likelihood that the variant does not have clinical significance. The c.11017-3C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition four of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

PKD1-related disorder Benign:1

Aug 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	-0.51
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		7.0
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0077
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.11		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: rs185355445; hg19: chr16-2143097;