rs367983387

Positions:

Variant summary

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

The ENST00000262304.9(PKD1):c.1710C>T(p.His570=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 1,540,920 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 42 hom. )

Consequence

PKD1
ENST00000262304.9 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.710

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=-0.88).

BP6

Variant 16-2116541-G-A is Benign according to our data. Variant chr16-2116541-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2116541-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.71 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00566 (862/152282) while in subpopulation NFE AF= 0.00776 (528/68006). AF 95% confidence interval is 0.00722. There are 2 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 862 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.1710C>T	p.His570=	synonymous_variant	8/46	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.1710C>T	p.His570=	synonymous_variant	8/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.1710C>T	p.His570=	synonymous_variant	8/46	1		ENSP00000399501	A2	P98161-3
PKD1	ENST00000488185.2 linkuse as main transcript	c.472+948C>T		intron_variant		5		ENSP00000456672
PKD1	ENST00000568591.5 linkuse as main transcript	c.*38C>T		3_prime_UTR_variant, NMD_transcript_variant	4/12	2		ENSP00000457162

Frequencies

GnomAD3 genomes

AF:

0.00566

AC:

862

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0231

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00776

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00498

AC:

857

AN:

172122

Hom.:

AF XY:

0.00530

AC XY:

497

AN XY:

93836

show subpopulations

Gnomad AFR exome

AF:

0.000841

Gnomad AMR exome

AF:

0.000393

Gnomad ASJ exome

AF:

0.00320

Gnomad EAS exome

AF:

0.0000750

Gnomad SAS exome

AF:

0.00307

Gnomad FIN exome

AF:

0.0208

Gnomad NFE exome

AF:

0.00691

Gnomad OTH exome

AF:

0.00296

GnomAD4 exome

AF:

0.00646

AC:

8976

AN:

1388638

Hom.:

Cov.:

AF XY:

0.00644

AC XY:

4436

AN XY:

688646

show subpopulations

Gnomad4 AFR exome

AF:

0.000880

Gnomad4 AMR exome

AF:

0.000464

Gnomad4 ASJ exome

AF:

0.00376

Gnomad4 EAS exome

AF:

0.0000271

Gnomad4 SAS exome

AF:

0.00284

Gnomad4 FIN exome

AF:

0.0220

Gnomad4 NFE exome

AF:

0.00689

Gnomad4 OTH exome

AF:

0.00530

GnomAD4 genome

AF:

0.00566

AC:

862

AN:

152282

Hom.:

Cov.:

AF XY:

0.00600

AC XY:

447

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00135

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0231

Gnomad4 NFE

AF:

0.00776

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00556

Hom.:

Bravo

AF:

0.00382

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 23, 2021	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PKD1: BP4, BP7, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 01, 2017

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.His570His variant was identified in 8 of 860 proband chromosomes (frequency: 0.009) from individuals or families with ADPKD (Rossetti 2001, Rossetti 2002, Rossetti 2012, Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs367983387) as â€šÃ„ÃºNAâ€šÃ„Ã¹, Clinvitae (classified as variant of unknown significance by Emory Genetics), and in the ADPKD Mutation Database (classification likely neutral); in the 1000 Genomes Project in 17 of 5000 chromosomes (frequency: 0.0034), in HAP-MAP: HAPMAP-EUR in 15 of 1006 chromosomes (frequency: 0.0149), HAPMAP-AMR in 1 of 694 chromosomes (frequency: 0.0014), HAPMAP-EAS in 1 of 1008 chromosomes (frequency: 0.001), NHLBI GO Exome Sequencing Project (ESP) in 40 of 8462 (frequency: 0.0047) European American, and in 3 of 4308 (frequency: 0.0007) African American alleles. The variant was also identified in the Exome Aggregation Consortium database (March 14, 2016) in 19 of 130 chromosomes (frequency: 0.1462) from a population of European (Finnish) individuals, in 164 (2 homozygous) of 7450 chromosomes (frequency: 0.02201) from a population of European (Non-Finnish) individuals, in 34 of 8056 chromosomes (frequency: 0.0042) from a population of South Asians, and in 3 of 1762 chromosomes (frequency: 0.0017) from a population of African individuals, increasing the likelihood this could be a low frequency benign variant. The variant was not seen in the East Asian, Other or Latino poulations. The variant was identified by our laboratory in a patient with PKD with a co-occurring pathogenic PKD1 variant (c.8388T>G, p.Tyr2796X), increasing the likelihood that the p.His570His variant does not have clinical significance. The p.His570His 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, this variant meets our laboratory criteria to be classified as benign. -

PKD1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.5

DANN

Benign

0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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