rs534696523

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000262304.9(PKD1):c.8161+5C>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,517,210 control chromosomes in the GnomAD database, including 1 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 0.00059 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

PKD1
ENST00000262304.9 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.0004212

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: -1.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 16-2104493-G-A is Benign according to our data. Variant chr16-2104493-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2104493-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.8161+5C>T		splice_donor_5th_base_variant, intron_variant		ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.8161+5C>T		splice_donor_5th_base_variant, intron_variant		1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.000592

AC:

AN:

148686

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000761

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00239

Gnomad ASJ

AF:

0.000871

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000213

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000193

Gnomad OTH

AF:

0.00243

GnomAD3 exomes

AF:

0.000145

AC:

AN:

151226

Hom.:

AF XY:

0.000171

AC XY:

AN XY:

81876

show subpopulations

Gnomad AFR exome

AF:

0.000398

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.000479

Gnomad EAS exome

AF:

0.0000837

Gnomad SAS exome

AF:

0.0000431

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.000191

AC:

262

AN:

1368410

Hom.:

Cov.:

AF XY:

0.000187

AC XY:

127

AN XY:

677670

show subpopulations

Gnomad4 AFR exome

AF:

0.000989

Gnomad4 AMR exome

AF:

0.000326

Gnomad4 ASJ exome

AF:

0.000801

Gnomad4 EAS exome

AF:

0.000109

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000171

Gnomad4 OTH exome

AF:

0.000246

GnomAD4 genome

AF:

0.000591

AC:

AN:

148800

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

72622

show subpopulations

Gnomad4 AFR

AF:

0.000759

Gnomad4 AMR

AF:

0.00239

Gnomad4 ASJ

AF:

0.000871

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000213

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000193

Gnomad4 OTH

AF:

0.00240

Alfa

AF:

0.000268

Hom.:

Bravo

AF:

0.000820

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 c.8161+5C>T variant was not identified in the literature nor was it identified in GeneInsight-COGR, LOVD 3.0, ADPKD Mutation Database or PKD1-LOVD. The variant was identified in dbSNP (ID: rs534696523) â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, ClinVar (classified likely benign by Prevention Genetics), and in control databases in 34 of 174976 chromosomes at a frequency of 0.0002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 6 of 15076 chromosomes (freq: 0.0004), Latino in 4 of 25344 chromosomes (freq: 0.0002), European Non-Finnish in 17 of 71256 chromosomes (freq: 0.0002), Ashkenazi Jewish in 5 of 8382 chromosomes (freq: 0.0006), East Asian in 1 of 12724 chromosomes (freq: 0.00008), and South Asian in 1 of 23284 chromosomes (freq: 0.00004), while not observed in the Other and European Finnish populations. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The c.8161+5C>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. Positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing; however, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing for the variant. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

PKD1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.90

DANN

Benign

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00042

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

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