chr16-2093096-G-A

Position:

chr16-2093096-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001009944.3(PKD1):c.11017-3C>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.007748

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 6.97

Variant links:

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 links:

PKD1-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

PKD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BS2

High AC in GnomAd4 at 203 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.11017-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262304.9	NP_001009944.3
PKD1-AS1	NR_135175.1 linkuse as main transcript	n.303+84G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.11017-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001009944.3	ENSP00000262304	P5	P98161-1
PKD1-AS1	ENST00000563284.3 linkuse as main transcript	n.194+84G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152202

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00106

AC:

264

AN:

248590

Hom.:

AF XY:

0.00101

AC XY:

136

AN XY:

135308

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.00231

AC XY:

1676

AN XY:

726292

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000615

Gnomad4 NFE exome

AF:

0.00294

Gnomad4 OTH exome

AF:

0.00267

GnomAD4 genome

AF:

0.00133

AC:

203

AN:

152320

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.00245

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00165

Hom.:

Bravo

AF:

0.00127

EpiCase

AF:

0.00213

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PKD1: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2021	In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 22367170, 27535533, 18640754) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 29, 2017

- -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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 â€šÃ„ÃºNAâ€šÃ„Ã¹, 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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

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

DANN

Benign

0.77

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over