rs141557400

Variant summary

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

The NM_001009944.3(PKD1):c.4845C>T(p.Asn1615=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 1,612,636 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0053 ( 22 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.162

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 16-2110322-G-A is Benign according to our data. Variant chr16-2110322-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110322-G-A is described in Lovd as [Benign]. Variant chr16-2110322-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.162 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00527 (7689/1460300) while in subpopulation NFE AF= 0.0064 (7117/1111820). AF 95% confidence interval is 0.00628. There are 22 homozygotes in gnomad4_exome. There are 3767 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.

BS2

High AC in GnomAd at 527 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.4845C>T	p.Asn1615=	synonymous_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.4845C>T	p.Asn1615=	synonymous_variant	15/46	1	NM_001009944.3	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00346

AC:

527

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00310

AC:

773

AN:

249432

Hom.:

AF XY:

0.00309

AC XY:

418

AN XY:

135478

show subpopulations

Gnomad AFR exome

AF:

0.000746

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00441

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00515

Gnomad OTH exome

AF:

0.00312

GnomAD4 exome

AF:

0.00527

AC:

7689

AN:

1460300

Hom.:

Cov.:

AF XY:

0.00519

AC XY:

3767

AN XY:

726440

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00219

Gnomad4 ASJ exome

AF:

0.00425

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000962

Gnomad4 FIN exome

AF:

0.000538

Gnomad4 NFE exome

AF:

0.00640

Gnomad4 OTH exome

AF:

0.00369

GnomAD4 genome

AF:

0.00346

AC:

527

AN:

152336

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

240

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.00477

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00559

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00468

Hom.:

Bravo

AF:

0.00372

EpiCase

AF:

0.00431

EpiControl

AF:

0.00569

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PKD1: BP4, BP7 -
Likely 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	Jul 17, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2021	This variant is associated with the following publications: (PMID: 22383692) -

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:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 24, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 08, 2021	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Asn1615= variant was identified in 1 of 460 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Rossetti_2012_22383692). The variant was also identified in dbSNP (ID: rs141557400) â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar (benign by Prevention Genetics), and ADPKD Mutation Database (classified likely neutral), and was not identified in GeneInsight-COGR, LOVD 3.0, and PKD1-LOVD. The variant was identified in control databases in 854 (1 homozygous) of 275992 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 18 of 23922 chromosomes (freq: 0.0008), Other in 17 of 6442 chromosomes (freq: 0.003), Latino in 76 of 34408 chromosomes (freq: 0.002), European Non-Finnish in 650 (1 homozygous) of 125708 chromosomes (freq: 0.005), Ashkenazi Jewish in 43 of 10106 chromosomes (freq: 0.004), European Finnish in 14 of 25786 chromosomes (freq: 0.0005), and South Asian in 36 of 30776 chromosomes (freq: 0.001). while not observed in the East Asian population. 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.Asn1615= 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 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

-0.59

Cadd

Benign

0.47

Dann

Benign

0.76

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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