rs140189010

Positions:

chr16-2097420-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.10304G>A(p.Arg3435Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00512 in 1,608,934 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 27 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.52

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044742227).

BP6

Variant 16-2097420-C-T is Benign according to our data. Variant chr16-2097420-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2097420-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00533 (7765/1456564) while in subpopulation NFE AF= 0.00671 (7461/1111888). AF 95% confidence interval is 0.00658. There are 27 homozygotes in gnomad4_exome. There are 3735 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 473 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.10304G>A	p.Arg3435Gln	missense_variant	33/46	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.10304G>A	p.Arg3435Gln	missense_variant	33/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.10301G>A	p.Arg3434Gln	missense_variant	33/46	1		ENSP00000399501	A2	P98161-3
PKD1	ENST00000487932.5 linkuse as main transcript	c.*1497G>A		3_prime_UTR_variant, NMD_transcript_variant	20/30	5		ENSP00000457132

Frequencies

GnomAD3 genomes

AF:

0.00311

AC:

473

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00575

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00242

AC:

591

AN:

244014

Hom.:

AF XY:

0.00235

AC XY:

313

AN XY:

133260

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.000202

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00466

Gnomad OTH exome

AF:

0.00249

GnomAD4 exome

AF:

0.00533

AC:

7765

AN:

1456564

Hom.:

Cov.:

AF XY:

0.00515

AC XY:

3735

AN XY:

724850

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00114

Gnomad4 NFE exome

AF:

0.00671

Gnomad4 OTH exome

AF:

0.00310

GnomAD4 genome

AF:

0.00310

AC:

473

AN:

152370

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

196

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00575

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00471

Hom.:

Bravo

AF:

0.00308

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00274

AC:

ESP6500EA

AF:

0.00606

AC:

ExAC

AF:

0.00224

AC:

271

EpiCase

AF:

0.00420

EpiControl

AF:

0.00445

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 05, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2020	This variant is associated with the following publications: (PMID: 27567292) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PKD1: BP4, BS2 -

Polycystic kidney disease, adult type

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 17, 2021	- -

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.Arg3435Gln variant was identified in 6 of 460 proband chromosomes (frequency: 0.01) from individuals with autosomal dominant polycystic kidney disease (Rossetti 2012). The variant was also identified in dbSNP (rs140189010) as â€šÃ„Ãºwith likely benign alleleâ€šÃ„Ã¹, ClinVar (interpreted as "likely benign" by PreventionGenetics and 1 other submitter), LOVD 3.0 and ADPKD Mutation Database. The variant was not identified in PKD1-LOVD. The variant was identified in control databases in 693 of 271,186 chromosomes at a frequency of 0.003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 25 of 23,576 chromosomes (freq: 0.001), Other in 11 of 6390 chromosomes (freq: 0.002), Latino in 19 of 34,358 chromosomes (freq: 0.0005), European in 609 of 124,992 chromosomes (freq: 0.005), Ashkenazi Jewish in 2 of 10,044 chromosomes (freq: 0.0002), Finnish in 26 of 22,306 chromosomes (freq: 0.001) and South Asian in 1 of 30,740 chromosomes (freq: 0.00003); it was not observed in the East Asian population. The p.Arg3435 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

PKD1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2020

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

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.037

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-2.0

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

0.050

N;N

REVEL

Benign

0.067

Sift

Benign

0.81

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0080

B;B

Vest4

0.13

MVP

0.39

ClinPred

0.0026

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.020

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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