rs145955373

chr16-2092112-G-Achr16-2092112-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):c.11346C>T(p.Asp3782=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0039 in 1,612,888 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (29 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0510

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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 16-2092112-G-A is Benign according to our data. Variant chr16-2092112-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2092112-G-A is described in Lovd as [Benign]. Variant chr16-2092112-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.051 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00393 (5742/1460560) while in subpopulation MID AF= 0.0184 (106/5768). AF 95% confidence interval is 0.0155. There are 29 homozygotes in gnomad4_exome. There are 3064 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 553 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.11346C>T	p.Asp3782=	synonymous_variant	40/46	ENST00000262304.9
PKD1-AS1	NR_135175.1	n.179+498G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.11346C>T	p.Asp3782=	synonymous_variant	40/46	1	NM_001009944.3	P5
PKD1-AS1	ENST00000563284.3	n.70+504G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 553 AN: 152210 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00562

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00455 AC: 1135 AN: 249620 Hom.: 5 AF XY: 0.00504 AC XY: 683 AN XY: 135614

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00340

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00879

Gnomad FIN exome AF: 0.00439

Gnomad NFE exome AF: 0.00508

Gnomad OTH exome AF: 0.00673

GnomAD4 exome AF: 0.00393 AC: 5742 AN: 1460560 Hom.: 29 Cov.: 33 AF XY: 0.00422 AC XY: 3064 AN XY: 726584

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00875

Gnomad4 FIN exome AF: 0.00529

Gnomad4 NFE exome AF: 0.00365

Gnomad4 OTH exome AF: 0.00475

GnomAD4 genome AF: 0.00363 AC: 553 AN: 152328 Hom.: 2 Cov.: 33 AF XY: 0.00332 AC XY: 247 AN XY: 74478

Gnomad4 AFR AF: 0.00151

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00562

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00354 Hom.: 0

Bravo AF: 0.00319

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00628

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2019	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2019	This variant is associated with the following publications: (PMID: 27401137, 19686598) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PKD1: BP4, BP7 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Asp3782Asp variant was identified as polymorphism in 6 of 550 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Rossetti 2012, Rossetti 2002). The variant was also identified in the following databases: in dbSNP (ID: rs145955373) as “With Benign allele”, ClinVar (1x, as benign by Prevention Genetics), ADPKD Mutation Database (as likely neutral). The variant was not identified in LOVD 3.0, or PKD1-LOVD databases. The variant was identified in control databases in 1274 of 276110 (5 homozygous) chromosomes at a frequency of 0.004614 in the following populations: African in 30 of 23896 chromosomes (freq. 0.0012), other in 40 of 6440 chromosomes (freq. 0.006), Latino in 106 of 34408 chromosomes (freq. 0.003), European in 669 of 125862 (2 homozygous) chromosomes (freq. 0.005), Ashkenazi Jewish in 36 of 10114 chromosomes (freq. 0.0035), East Asian in 1 of 18836 chromosomes (freq. 0.00005), Finnish in 118 of 25778 chromosomes (freq. 0.0045),and South Asian in 274 of 30776 (3 homozygous) chromosomes (freq. 0.009), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Asp3782Asp variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. A co-occurring pathogenic PKD1 variant (c.7864-1G>T, r.spl?) is identified in 1 individual with ADPKD in our laboratory, increasing the likelihood that p.Asp3782=variant does not have clinical significance. 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	-0.77
Cadd	Benign	5.9
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs145955373; hg19: chr16-2142113; COSMIC: COSV99238896; COSMIC: COSV99238896;