rs114846412

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001009944.3(PKD1):c.2854-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00589 in 1,594,686 control chromosomes in the GnomAD database, including 507 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 Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 268 hom., cov: 29)

Exomes 𝑓: 0.0034 ( 239 hom. )

Consequence

PKD1
NM_001009944.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00004595

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -3.06

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 16-2113297-G-A is Benign according to our data. Variant chr16-2113297-G-A is described in ClinVar as [Benign]. Clinvar id is 256938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2113297-G-A is described in Lovd as [Benign]. Variant chr16-2113297-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.2854-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.2854-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001009944.3	P5	P98161-1
	ENST00000568795.1 linkuse as main transcript	n.411G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0299

AC:

4532

AN:

151614

Hom.:

268

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000418

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000765

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.00880

AC:

1825

AN:

207342

Hom.:

AF XY:

0.00629

AC XY:

710

AN XY:

112830

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.00623

Gnomad ASJ exome

AF:

0.00106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000204

Gnomad FIN exome

AF:

0.000104

Gnomad NFE exome

AF:

0.000512

Gnomad OTH exome

AF:

0.00266

GnomAD4 exome

AF:

0.00336

AC:

4853

AN:

1442956

Hom.:

239

Cov.:

AF XY:

0.00286

AC XY:

2052

AN XY:

718284

show subpopulations

Gnomad4 AFR exome

AF:

0.107

Gnomad4 AMR exome

AF:

0.00729

Gnomad4 ASJ exome

AF:

0.000880

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.0000528

Gnomad4 NFE exome

AF:

0.000359

Gnomad4 OTH exome

AF:

0.00797

GnomAD4 genome

AF:

0.0299

AC:

4537

AN:

151730

Hom.:

268

Cov.:

AF XY:

0.0285

AC XY:

2114

AN XY:

74168

show subpopulations

Gnomad4 AFR

AF:

0.103

Gnomad4 AMR

AF:

0.0103

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000418

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000765

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.00189

Hom.:

Bravo

AF:

0.0341

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2019	This variant is associated with the following publications: (PMID: 11967008, 22008521) -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 02, 2020

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 c.2854-5T>C variant was identified in 3 of 164 proband chromosomes (freq: 0.018) from individuals or families with ADPKD, and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011, Rossetti 2002). The variant is also identified in dbSNP (ID: rs114846412) with no Allele status indicated. In addition, this variant was identified in the 1000 Genomes Project in 193 of 5013 chromosomes (freq: 0.0385), in the NHLBI GO Exome Sequencing Project in 4 of 4820 (frequency: 0.0008) European American, 286 of 2764 African American alleles (frequency: 0.1035) and in the Exome Aggregation Consortium database (Mar 14, 2016) in in 983 of 100432 chromosomes (freq. 0.010) in the following populations: African in 884 (48 homozygous) of 7940 chromosomes (freq. 0.11), other in 4 of 678 chromosomes (freq. 0.006), Latino in 62 of 11132 chromosomes (freq. 0.006), European (Non-Finnish) in 33 of 57550 chromosomes (freq. 0.0006), but was not seen in East Asian, Finnish, and South Asian populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. We cannot be certain that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant is also identified in GeneInsight COGR (1x as benign), and in ADPKD Mutation Database (4x as likely neutral). The c.2854-5T>C 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 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 criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.056

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000046

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.020

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