rs45478794

Positions:

chr16-2094181-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001009944.3(PKD1):c.10529C>T(p.Thr3510Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,605,754 control chromosomes in the GnomAD database, including 645 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 45 hom., cov: 33)

Exomes 𝑓: 0.013 ( 600 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.865

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-AS1 (HGNC:):

PKD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022667646).

BP6

Variant 16-2094181-G-A is Benign according to our data. Variant chr16-2094181-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2094181-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.10529C>T	p.Thr3510Met	missense_variant	35/46	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.10529C>T	p.Thr3510Met	missense_variant	35/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1621

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.0575

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.00621

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00855

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.0209

AC:

4944

AN:

236058

Hom.:

191

AF XY:

0.0248

AC XY:

3191

AN XY:

128610

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00319

Gnomad ASJ exome

AF:

0.00177

Gnomad EAS exome

AF:

0.0579

Gnomad SAS exome

AF:

0.0941

Gnomad FIN exome

AF:

0.00694

Gnomad NFE exome

AF:

0.00730

Gnomad OTH exome

AF:

0.0136

GnomAD4 exome

AF:

0.0135

AC:

19585

AN:

1453432

Hom.:

600

Cov.:

AF XY:

0.0160

AC XY:

11534

AN XY:

722754

show subpopulations

Gnomad4 AFR exome

AF:

0.00204

Gnomad4 AMR exome

AF:

0.00314

Gnomad4 ASJ exome

AF:

0.00185

Gnomad4 EAS exome

AF:

0.0521

Gnomad4 SAS exome

AF:

0.0944

Gnomad4 FIN exome

AF:

0.00669

Gnomad4 NFE exome

AF:

0.00715

Gnomad4 OTH exome

AF:

0.0149

GnomAD4 genome

AF:

0.0106

AC:

1614

AN:

152322

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

938

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00200

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.0575

Gnomad4 SAS

AF:

0.103

Gnomad4 FIN

AF:

0.00621

Gnomad4 NFE

AF:

0.00856

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00965

Hom.:

Bravo

AF:

0.00803

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.00652

AC:

ExAC

AF:

0.0211

AC:

2547

Asia WGS

AF:

0.0500

AC:

175

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Polycystic kidney disease 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 03, 2020	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	This variant is associated with the following publications: (PMID: 32823016, 11558899, 11691639, 12007219, 18640754, 19686598, 28578020, 27499327, 26632257, 26722532, 18067079, 20981092, 22185115) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Thr3510Met variant was identified in 25 of 1248 proband chromosomes (frequency: 0.020) from Japanese, Chinese and Czech individuals or families with ADPKD, and was identified in 6 of 200 control chromosomes from healthy individuals (Mizoguchi 2001, Inoue 2002, Reed 2008, Rossetti 2001, Tsuchiya 2001, Yu 2011, Stekrova 2009). The variant was identified with a co-occurring pathogenic PKD1 variant (Q2142X), increasing the likelihood that the p.Thr3510Met variant does not have clinical significance (Yu 2011). The variant was also identified in dbSNP (ID: rs45478794) â€šÃ„ÃºWith NA alleleâ€šÃ„Ã¹, ADPKD Mutation Database (classification likely neutral), 1000 Genomes Project in 192 of 5013 chromosomes (frequency: 0.0383); HAP-MAP populations: SAS in 120 of 978 chromosomes (frequency: 0.1227)/EAS in 63 of 1008 chromosomes (frequency: 0.0625)/EUR in 8 of 1006 chromosomes (frequency: 0.008), in the NHLBI GO Exome Sequencing Project (ESP) in 56 of 8588 (frequency: 0.0065) European American and in 12 OF 4388 (frequency: 0.0027)African American alleles, and in all populations in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015): South Asian in 1466 (87 homozygous) of 130000 chromosomes (frequency: 0.1128), East Asian in 432 (11 homozygous) of 6452 chromosomes (frequency: 0.0067), Other in 15 of 600 chromosomes (frequency: 0.025), European (Non-Finnish) in 388 (2 homozygous) of 45098 chromosomes (frequency: 0.0086), European (Finnish) in 26 of 3626 chromosomes (frequency: 0.0071), Latino in 43 of 7878 chromosomes (frequency: 0.0054) and African in 18 (1 homozygous) of 6646 chromosomes (frequency: 0.0027), increasing the likelihood this could be a low frequency benign variant.The p.Thr3510Met residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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 summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Likely benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.68

CADD

Benign

6.8

DANN

Benign

0.89

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.67

N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.10

Sift

Benign

0.047

D;D

Sift4G

Benign

0.080

T;T

Polyphen

0.86

P;P

Vest4

0.039

ClinPred

0.0025

GERP RS

0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.018

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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