chr16-2115629-T-C

Position:

chr16-2115629-T-C

Variant summary

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

The NM_001009944.3(PKD1):c.1850-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,579,892 control chromosomes in the GnomAD database, including 31,130 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 0.25 ( 6595 hom., cov: 32)

Exomes 𝑓: 0.17 ( 24535 hom. )

Consequence

PKD1
NM_001009944.3 splice_region, intron

Scores

Splicing: ADA: 0.00003932

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.944

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=-0.91).

BP6

Variant 16-2115629-T-C is Benign according to our data. Variant chr16-2115629-T-C is described in ClinVar as [Benign]. Clinvar id is 256929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2115629-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.1850-4A>G		splice_region_variant, intron_variant		ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
PKD1	ENST00000262304.9 link	c.1850-4A>G	splice_region_variant, intron_variant	1	NM_001009944.3	ENSP00000262304.4	P98161-1
PKD1	ENST00000423118.5 link	c.1850-4A>G	splice_region_variant, intron_variant	1		ENSP00000399501.1	P98161-3
PKD1	ENST00000488185.2 link	c.470+1860A>G	intron_variant	5		ENSP00000456672.1	H3BSE9
PKD1	ENST00000568591.5 link	n.*178-4A>G	splice_region_variant, intron_variant	2		ENSP00000457162.1	H3BTG3

Frequencies

GnomAD3 genomes

AF:

0.255

AC:

38647

AN:

151776

Hom.:

6574

Cov.:

show subpopulations

Gnomad AFR

AF:

0.478

Gnomad AMI

AF:

0.135

Gnomad AMR

AF:

0.195

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.0752

Gnomad FIN

AF:

0.194

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.177

Gnomad OTH

AF:

0.250

GnomAD3 exomes

AF:

0.155

AC:

34502

AN:

223140

Hom.:

3789

AF XY:

0.150

AC XY:

18556

AN XY:

123352

show subpopulations

Gnomad AFR exome

AF:

0.474

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.230

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.0714

Gnomad FIN exome

AF:

0.161

Gnomad NFE exome

AF:

0.170

Gnomad OTH exome

AF:

0.177

GnomAD4 exome

AF:

0.170

AC:

242571

AN:

1427998

Hom.:

24535

Cov.:

AF XY:

0.167

AC XY:

118540

AN XY:

710856

show subpopulations

Gnomad4 AFR exome

AF:

0.486

Gnomad4 AMR exome

AF:

0.122

Gnomad4 ASJ exome

AF:

0.237

Gnomad4 EAS exome

AF:

0.000303

Gnomad4 SAS exome

AF:

0.0748

Gnomad4 FIN exome

AF:

0.181

Gnomad4 NFE exome

AF:

0.173

Gnomad4 OTH exome

AF:

0.183

GnomAD4 genome

AF:

0.255

AC:

38711

AN:

151894

Hom.:

6595

Cov.:

AF XY:

0.250

AC XY:

18531

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.478

Gnomad4 AMR

AF:

0.194

Gnomad4 ASJ

AF:

0.240

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.0746

Gnomad4 FIN

AF:

0.194

Gnomad4 NFE

AF:

0.177

Gnomad4 OTH

AF:

0.247

Alfa

AF:

0.216

Hom.:

856

Bravo

AF:

0.266

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	This variant is associated with the following publications: (PMID: 17574468, 22008521, 22383692, 22608885, 18837007) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Jul 07, 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.1850-4A>G variant was identified in 113 of 698 proband chromosomes (frequency: 0.162) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2012 ). The variant was also identified in dbSNP (ID: rs35929659) â€šÃ„ÃºWith unknown alleleâ€šÃ„Ã¹, ADPKD Mutation Database (classification likely neutral), 1000 Genomes Project in 1135 of 5009 chromosomes (frequency: 0.2266), HAPMAP-AFR in 728 of 1322 chromosomes (frequency: 0.5507)/HAPMAP-AMR in 137 of 694 chromosomes (frequency: 0.1974)/HAPMAP-EUR in 185 of 1006 chromosomes (frequency: 0.1839), NHLBI GO Exome Sequencing Project (ESP) in 1196 of 8014 European American (frequency: 0.15) and in 1527 of 3938 African American alleles (frequency: 0.39), and the Exome Aggregation Consortium (ExAC) database (Jan 13, 2015) in 15580 of 82726 (1701 being homozygous) chromosomes (frequency: 0.1883) with individuals from all populations;European (Non-Finnish), East Asian, Other, African, Latino, South Asian, and European (Finnish). The c.1850-4A>G 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. 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 a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. REFERENCES: Bataille S, Berland Y, Fontes M, Burtey S. High Resolution Melt analysis for mutation screening in PKD1 and PKD2. BMC Nephrol. 2011 Oct 18;12:57. doi: 10.1186/1471-2369-12-57. PubMed PMID: 22008521; PubMed Central PMCID: PMC3206831. Garcia-Gonzalez MA, Jones JG, Allen SK, Palatucci CM, Batish SD, Seltzer WK, Lan Z, Allen E, Qian F, Lens XM, Pei Y, Germino GG, Watnick TJ. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab. 2007 Sep-Oct;92(1-2):160-7. Epub 2007 Jun 18. PubMed PMID: 17574468; PubMed Central PMCID: PMC2085355. Rossetti S, Hopp K, Sikkink RA, Sundsbak JL, Lee YK, Kubly V, Eckloff BW, Ward CJ, Winearls CG, Torres VE, Harris PC. Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol. 2012 May;23(5):915-33. doi: 10.1681/ASN.2011101032. Epub 2012 Mar 1. PubMed PMID: 22383692; PubMed Central PMCID: PMC3338301. -

Autosomal dominant polycystic kidney disease

Benign:1

Benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.73

DANN

Benign

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000039

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

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