rs199700485

Positions:

chr16-2104530-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000262304.9(PKD1):c.8129C>A(p.Thr2710Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000554 in 1,567,470 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00056 ( 1 hom. )

Consequence

PKD1
ENST00000262304.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 6.21

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 Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.8129C>A	p.Thr2710Asn	missense_variant	22/46	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.8129C>A	p.Thr2710Asn	missense_variant	22/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.000466

AC:

AN:

150138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000529

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000473

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000754

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000315

AC:

AN:

152168

Hom.:

AF XY:

0.000317

AC XY:

AN XY:

82014

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000321

Gnomad NFE exome

AF:

0.000708

Gnomad OTH exome

AF:

0.000460

GnomAD4 exome

AF:

0.000563

AC:

798

AN:

1417332

Hom.:

Cov.:

AF XY:

0.000542

AC XY:

381

AN XY:

703060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000248

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000397

Gnomad4 NFE exome

AF:

0.000688

Gnomad4 OTH exome

AF:

0.000495

GnomAD4 genome

AF:

0.000466

AC:

AN:

150138

Hom.:

Cov.:

AF XY:

0.000396

AC XY:

AN XY:

73250

show subpopulations

Gnomad4 AFR

AF:

0.000149

Gnomad4 AMR

AF:

0.000529

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000473

Gnomad4 NFE

AF:

0.000754

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000421

Hom.:

Bravo

AF:

0.000438

ExAC

AF:

0.000409

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2022	Reported in a family with autosomal dominant polycystic kidney disease in published literature (Nielsen et al., 2021); however, no patient-specific clinical information provided; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33639313) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PKD1: BP4, BS2 -

Polycystic kidney disease, adult type

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Dec 16, 2019

- -

Polycystic kidney disease

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Thr2710Asn variant was not identified in the literature nor was it identified in the NHLBI GO Exome Sequencing Project, Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD and PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs199700485) as â€šÃ„ÃºNAâ€šÃ„Ã¹, Exome Aggregation Consortium database (March 14, 2016) in 10 of 17162 chromosomes (freq. 0.0005827) in the following populations: European (Non-Finnish) in 10 of 6286 chromosomes (freq. 0.001591), but was not seen in African, East Asian, European (Finnish), Latino, South Asian and Other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. 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 variant was identified in ADPKD Mutation Database (likely pathogenic). The p.Thr2710 residue is 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. The identification of this variant as co-occurring with a likely pathogenic variant by our laboratory in an individual with polycystic kidney disease increases the likelihood this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

D;.

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.92

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.5

D;N

REVEL

Benign

0.18

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.50

MVP

0.90

ClinPred

0.21

GERP RS

3.3

Varity_R

0.31

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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