rs144557371

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001009944.3(PKD1):c.8020C>T(p.Pro2674Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,514,628 control chromosomes in the GnomAD database, including 176 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 ( 16 hom., cov: 19)

Exomes 𝑓: 0.014 ( 160 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.911

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=0.0047415793).

BP6

Variant 16-2104639-G-A is Benign according to our data. Variant chr16-2104639-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2104639-G-A is described in Lovd as [Benign]. Variant chr16-2104639-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0109 (1574/144690) while in subpopulation NFE AF= 0.0161 (1066/66028). AF 95% confidence interval is 0.0153. There are 16 homozygotes in gnomad4. There are 736 alleles in male gnomad4 subpopulation. Median coverage is 19. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1574 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8020C>T	p.Pro2674Ser	missense_variant	Exon 22 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.8020C>T	p.Pro2674Ser	missense_variant	Exon 22 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1573

AN:

144572

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00209

Gnomad AMI

AF:

0.00222

Gnomad AMR

AF:

0.00560

Gnomad ASJ

AF:

0.00560

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000682

Gnomad FIN

AF:

0.0309

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0161

Gnomad OTH

AF:

0.00507

GnomAD3 exomes

AF:

0.00937

AC:

1214

AN:

129502

Hom.:

AF XY:

0.00910

AC XY:

639

AN XY:

70208

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.00783

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000962

Gnomad FIN exome

AF:

0.0311

Gnomad NFE exome

AF:

0.0150

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.0136

AC:

18586

AN:

1369938

Hom.:

160

Cov.:

AF XY:

0.0134

AC XY:

9156

AN XY:

684118

show subpopulations

Gnomad4 AFR exome

AF:

0.00171

Gnomad4 AMR exome

AF:

0.00609

Gnomad4 ASJ exome

AF:

0.00733

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.000994

Gnomad4 FIN exome

AF:

0.0293

Gnomad4 NFE exome

AF:

0.0154

Gnomad4 OTH exome

AF:

0.0105

GnomAD4 genome

AF:

0.0109

AC:

1574

AN:

144690

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

736

AN XY:

70198

show subpopulations

Gnomad4 AFR

AF:

0.00208

Gnomad4 AMR

AF:

0.00559

Gnomad4 ASJ

AF:

0.00560

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000682

Gnomad4 FIN

AF:

0.0309

Gnomad4 NFE

AF:

0.0161

Gnomad4 OTH

AF:

0.00501

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.00849

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00786

AC:

ExAC

AF:

0.00321

AC:

228

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Dec 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22008521, 17574468, 11115377, 32457805) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 18, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:4

Jul 12, 2022

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type

Benign:2

Apr 04, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Pro2674Ser variant was identified in 11 of 586 proband chromosomes (frequency: 0.02) from individuals with Autosomal Dominant Polycystic Kidney Disease (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2001). The variant was identified in dbSNP (rs144557371) as â€šÃ„Ãºwith other alleleâ€šÃ„Ã¹, ClinVar (interpreted as likely benign by our laboratory and 1 other submitter; and as benign by ARUP Laboratories), LOVD 3.0 (observed 2x) and ADPKD Mutation Database (observed 1x). The variant was not identified in PKD1-LOVD. The variant was identified in control databases in 1570 of 151,230 chromosomes (10 homozygous) at a frequency of 0.01, 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 26 of 13,758 chromosomes (freq: 0.002), Other in 52 of 4316 chromosomes (freq: 0.01), Latino in 155 of 24,266 chromosomes (freq: 0.006), European in 986 of 60,346 chromosomes (freq: 0.01), Ashkenazi Jewish in 58 of 7264 chromosomes (freq: 0.008), Finnish in 273 of 9002 chromosomes (freq: 0.03), and South Asian in 20 of 20,846 chromosomes (freq: 0.001); it was 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.Pro2674 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, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.5

DANN

Benign

0.75

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.66

T;T

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.2

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.050

N;N

REVEL

Benign

0.050

Sift

Benign

0.59

T;T

Sift4G

Benign

0.73

T;T

Polyphen

0.0010

B;B

Vest4

0.11

MVP

0.42

ClinPred

0.0013

GERP RS

-2.5

Varity_R

0.034

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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