rs145737766

chr16-2111096-C-A

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.4071G>T(p.Leu1357=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00815 in 1,610,736 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0083 (91 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.438

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-2111096-C-A is Benign according to our data. Variant chr16-2111096-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 256961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2111096-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.438 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0063 (960/152338) while in subpopulation AMR AF= 0.0105 (161/15300). AF 95% confidence interval is 0.0092. There are 8 homozygotes in gnomad4. There are 431 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 959 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.4071G>T	p.Leu1357=	synonymous_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.4071G>T	p.Leu1357=	synonymous_variant	15/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00630 AC: 959 AN: 152220 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00978

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00602 AC: 1494 AN: 248048 Hom.: 13 AF XY: 0.00642 AC XY: 866 AN XY: 134932

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00533

Gnomad ASJ exome AF: 0.00261

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00990

Gnomad OTH exome AF: 0.00562

GnomAD4 exome AF: 0.00834 AC: 12162 AN: 1458398 Hom.: 91 Cov.: 36 AF XY: 0.00825 AC XY: 5984 AN XY: 725526

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00255

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.00986

Gnomad4 OTH exome AF: 0.00821

GnomAD4 genome AF: 0.00630 AC: 960 AN: 152338 Hom.: 8 Cov.: 33 AF XY: 0.00579 AC XY: 431 AN XY: 74488

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00979

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00865 Hom.: 5

Bravo AF: 0.00685

EpiCase AF: 0.0109

EpiControl AF: 0.0121

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PKD1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	This variant is associated with the following publications: (PMID: 17574468, 22008521, 22383692) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 20, 2020

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Leu1357Leu variant was identified in 8 of 698 proband chromosomes (frequency: 0.011) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs145737766) as “NA”, the ADPKD Mutation Database (as likely neutral), 1000 Genomes Project in 19 of 5000 chromosomes (frequency: 0.0038), the Exome Aggregation Consortium database (March 14, 2016) in 677 (11 homozygous) of 117978 chromosomes (freq. 0.006) in the following populations: European in 552 of 64394 chromosomes (freq. 0.009), Latino in 54 of 11464 chromosomes (freq. 0.005), South Asian in 45 of 16480 chromosomes (freq. 0.003), African in 13 of 9812 chromosomes (freq. 0.001), Finnish in 12 of 6442 chromosomes (freq. 0.002), Other in 1 of 8530 chromosomes (freq. 0.001), increasing the likelihood this could be a low frequency benign variant. 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 was not identified in Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. The p.Leu1357Leu 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. 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 addition, several PKD studies classify the variant as known exonic polymorphic variant (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2012). 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	-0.50
Cadd	Benign	0.70
Dann	Benign	0.67

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

Other links and lift over

dbSNP: rs145737766; hg19: chr16-2161097;