rs201704201

chr16-2111886-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001009944.3(PKD1):c.3296-15G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,609,728 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (15 hom.)
• Consequence: PKD1 NM_001009944.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.312

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-2111886-C-T is Benign according to our data. Variant chr16-2111886-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2111886-C-T is described in Lovd as [Benign]. Variant chr16-2111886-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 463 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.3296-15G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.3296-15G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 463 AN: 152174 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00290 AC: 700 AN: 241402 Hom.: 0 AF XY: 0.00261 AC XY: 345 AN XY: 132422

Gnomad AFR exome AF: 0.00153

Gnomad AMR exome AF: 0.00184

Gnomad ASJ exome AF: 0.00142

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00506

Gnomad OTH exome AF: 0.00357

GnomAD4 exome AF: 0.00446 AC: 6496 AN: 1457436 Hom.: 15 Cov.: 35 AF XY: 0.00427 AC XY: 3099 AN XY: 725088

Gnomad4 AFR exome AF: 0.000929

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000221

Gnomad4 FIN exome AF: 0.00158

Gnomad4 NFE exome AF: 0.00540

Gnomad4 OTH exome AF: 0.00389

GnomAD4 genome AF: 0.00304 AC: 463 AN: 152292 Hom.: 2 Cov.: 33 AF XY: 0.00266 AC XY: 198 AN XY: 74480

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00491

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00348 Hom.: 0

Bravo AF: 0.00339

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Polycystic kidney disease, adult type Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 03, 2018	- -

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.3296-15G>A variant was not identified in the literature nor was it identified in the GeneInsight-COGR, LOVD 3.0, PKD1-LOVD, databases. The variant was identified in dbSNP (ID: rs201704201) as “With Benign allele”; in the ClinVar database as benign by Prevention Genetics; in ADPKD Mutation Database 2X as likely neutral; in the 1000 Genomes Project in 4 of 5000 chromosomes (frequency: 0.0008); and in the NHLBI GO Exome Sequencing Project in 46 of 8572 European American (freq. 0.005) and in 10 of 4360 (freq. 0.002) African American alleles. The variant was identified in control databases in 779 of 269446 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). 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 variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 2 of 5, but this information is not very predictive of pathogenicity. In addition, this variant was identified in one individual from our laboratory with a co-occurring likely pathogenic variant in PKD2 (c.1898+5G>A), increasing the likelihood this variant does not have clinical significance. In summary, based on the above information this variant meets our laboratory criteria to be classified as likely benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

PKD1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.9
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs201704201; hg19: chr16-2161887;