rs147923678

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.8948+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,609,766 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 11 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 48 hom. )

Consequence

PKD1
NM_001009944.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.08

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 16-2102803-G-A is Benign according to our data. Variant chr16-2102803-G-A is described in ClinVar as [Benign]. Clinvar id is 257032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2102803-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8948+11C>T		intron_variant		ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.8948+11C>T		intron_variant		1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00285

AC:

434

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.0685

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00532

AC:

1315

AN:

247146

Hom.:

AF XY:

0.00486

AC XY:

653

AN XY:

134436

show subpopulations

Gnomad AFR exome

AF:

0.000191

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.000702

Gnomad EAS exome

AF:

0.0632

Gnomad SAS exome

AF:

0.000850

Gnomad FIN exome

AF:

0.00144

Gnomad NFE exome

AF:

0.000477

Gnomad OTH exome

AF:

0.00265

GnomAD4 exome

AF:

0.00184

AC:

2677

AN:

1457422

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

1329

AN XY:

724928

show subpopulations

Gnomad4 AFR exome

AF:

0.0000900

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.0509

Gnomad4 SAS exome

AF:

0.000824

Gnomad4 FIN exome

AF:

0.00158

Gnomad4 NFE exome

AF:

0.000254

Gnomad4 OTH exome

AF:

0.00297

GnomAD4 genome

AF:

0.00286

AC:

436

AN:

152344

Hom.:

Cov.:

AF XY:

0.00330

AC XY:

246

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.0691

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.00289

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 31, 2018

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 c.8948+11C>T variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, MutDB, PKD1-LOVD and PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs147923678) as â€šÃ„ÃºNAâ€šÃ„Ã¹ with a minor allele frequency of 0.0122 (61 of 5000 chromosomes) in the 1000 Genomes Project, NHLBI GO Exome Sequencing Project in 2 of 8574 European American and 1 of 4384 African American alleles, in the Exome Aggregation Consortium database (March 14, 2016) in 598 (18 homozygous) of 119030 chromosomes (freq. 0.005024) in the following populations: East Asian in 519 of 8604 chromosomes (freq. 0.06032), Finnish in 8 of 6588 chromosomes (freq. 0.001214), Latino in 12 of 11528 chromosomes (freq. 0.001041), South Asian in 16 of 16500 chromosomes (freq. 0.0009697), and European (Non-Finnish) in 40 of 65156 chromosomes (freq. 0.0006139), African in 2 of 9768 (freq. 0.0002048) and other in 1 of 886 (freq. 0.001129), increasing the likelihood this could be a low frequency benign variant. The variant was identified in GeneInsight COGR (Benign) and ADPKD Mutation Database (Likely neutral). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site; however, HumanSpliceFinder predicts an altered 5' splice site in this region, this information is not very predictive of pathogenicity. 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 benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.064

DANN

Benign

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

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