chr16-2110672-G-A

Position:

chr16-2110672-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001009944.3(PKD1):c.4495C>T(p.Leu1499Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,610,266 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 9 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.25

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:

PKD1 (HGNC:):

PKD1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 16-2110672-G-A is Benign according to our data. Variant chr16-2110672-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110672-G-A is described in Lovd as [Benign]. Variant chr16-2110672-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.25 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00314 (4581/1457900) while in subpopulation MID AF= 0.0101 (42/4152). AF 95% confidence interval is 0.00769. There are 9 homozygotes in gnomad4_exome. There are 2336 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.

BS2

High AC in GnomAd4 at 413 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.4495C>T	p.Leu1499Leu	synonymous_variant	15/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.4495C>T	p.Leu1499Leu	synonymous_variant	15/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

414

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00451

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00262

AC:

647

AN:

246570

Hom.:

AF XY:

0.00275

AC XY:

371

AN XY:

134718

show subpopulations

Gnomad AFR exome

AF:

0.000263

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00797

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.000466

Gnomad NFE exome

AF:

0.00381

Gnomad OTH exome

AF:

0.00450

GnomAD4 exome

AF:

0.00314

AC:

4581

AN:

1457900

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

2336

AN XY:

725154

show subpopulations

Gnomad4 AFR exome

AF:

0.000539

Gnomad4 AMR exome

AF:

0.00239

Gnomad4 ASJ exome

AF:

0.00605

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00114

Gnomad4 FIN exome

AF:

0.000538

Gnomad4 NFE exome

AF:

0.00352

Gnomad4 OTH exome

AF:

0.00357

GnomAD4 genome

AF:

0.00271

AC:

413

AN:

152366

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000673

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.00451

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00406

Hom.:

Bravo

AF:

0.00274

EpiCase

AF:

0.00600

EpiControl

AF:

0.00498

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 19, 2019	- -
Likely 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	-	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	This variant is associated with the following publications: (PMID: 18837007, 29860066) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	PKD1: BP4, BP7 -

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 02, 2020	- -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Leu1499= variant was identified in 5 of 578 proband chromosomes (frequency: 0.009) from individuals or families with ADPKD (Rossetti 2012, Tan 2009). The variant was also identified in the following databases: dbSNP (ID: rs142002333) as â€šÃ„Ãºwith Likely benign alleleâ€šÃ„Ã¹, ClinVar (classified as likely benign by Prevention Genetics), GeneInsight-COGR (classified as benign by a clinical laboratory - LMM), ADPKD Mutation Database (classified as likely neutral). The variant was not identified in LOVD 3.0, PKD1-LOVD, databases. The variant was identified in control databases in 713 (1 homozygous) of 274464 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 p.Leu1499= 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. 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 likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.46

DANN

Benign

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

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