rs149022148

Positions:

Variant summary

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

The NM_001009944.3(PKD1):c.1714C>T(p.Pro572Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,530,406 control chromosomes in the GnomAD database, including 550 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 306 hom., cov: 33)

Exomes 𝑓: 0.0034 ( 244 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.733

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=0.0021684766).

BP6

Variant 16-2116537-G-A is Benign according to our data. Variant chr16-2116537-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2116537-G-A is described in Lovd as [Benign]. Variant chr16-2116537-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.1714C>T	p.Pro572Ser	missense_variant	8/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.1714C>T	p.Pro572Ser	missense_variant	8/46	1	NM_001009944.3	P5	P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.1714C>T	p.Pro572Ser	missense_variant	8/46	1		A2	P98161-3
PKD1	ENST00000488185.2 linkuse as main transcript	c.472+952C>T		intron_variant		5
PKD1	ENST00000568591.5 linkuse as main transcript	c.*42C>T		3_prime_UTR_variant, NMD_transcript_variant	4/12	2

Frequencies

GnomAD3 genomes

AF:

0.0320

AC:

4873

AN:

152158

Hom.:

306

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.00784

AC:

1316

AN:

167828

Hom.:

AF XY:

0.00557

AC XY:

509

AN XY:

91384

show subpopulations

Gnomad AFR exome

AF:

0.117

Gnomad AMR exome

AF:

0.00677

Gnomad ASJ exome

AF:

0.00104

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000124

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000382

Gnomad OTH exome

AF:

0.00344

GnomAD4 exome

AF:

0.00339

AC:

4676

AN:

1378130

Hom.:

244

Cov.:

AF XY:

0.00288

AC XY:

1970

AN XY:

683460

show subpopulations

Gnomad4 AFR exome

AF:

0.113

Gnomad4 AMR exome

AF:

0.00748

Gnomad4 ASJ exome

AF:

0.000912

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000150

Gnomad4 FIN exome

AF:

0.0000244

Gnomad4 NFE exome

AF:

0.000288

Gnomad4 OTH exome

AF:

0.00822

GnomAD4 genome

AF:

0.0320

AC:

4880

AN:

152276

Hom.:

306

Cov.:

AF XY:

0.0308

AC XY:

2293

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.111

Gnomad4 AMR

AF:

0.0109

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.00967

Hom.:

Bravo

AF:

0.0364

ESP6500AA

AF:

0.0981

AC:

422

ESP6500EA

AF:

0.000474

AC:

ExAC

AF:

0.00713

AC:

836

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease, adult type

Benign:2

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	Jun 02, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2019	This variant is associated with the following publications: (PMID: 22383692, 22008521, 17574468, 11967008) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Pro572Ser variant was identified in 7 of 788 proband chromosomes (frequency: 0.009) from French, Spanish and North American individuals or families with ADPKD, occurring in the homozygous state in some probands (Bataille 2011, Rossetti 2002, Garcia-Gonzalez 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs149022148) as â€šÃ„ÃºNAâ€šÃ„Ã¹, ADPKD Mutation Database (classification Likely Neutral), and COSMIC (in an adenocarcinoma- large intestine), and not in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0 databases. The variant was identified in the 1000 Genomes Project in 204 of 5012 chromosomes (frequency: 0.0407), HAP-MAP populations: -AFR in 194 of 1322 chromosomes (frequency: 0.1467) and AMR in 10 of 694 chromosomes (frequency: 0.0144), NHLBI GO Exome Sequencing Project in 4 of 8440 (frequency: 0.0005) European American alleles and in 422 of 4300 African American alleles (frequency: 0.0981), and in the Exome Aggregation Consortium database (March 14 2016) in 382 of 18478 chromosomes (frequency 0.02) in the following populations: African in 360 (13 homozygous) of 1826 chromosomes (frequency: 0.1972), Latino in 16 of 680 chromosomes (frequency: 0.02353), Other in 1 of 174 chromosomes (frequency: 0006), European (Non-Finnish) in 4 of 6948 chromosomes (frequency: 0.0006), and South Asian in 1 of 8022 chromosomes (frequency: 0.0001), but was not seen in East Asian and Finnish populations, increasing the likelihood this could be a low frequency benign variant. The p.Pro572 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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

0.10

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.70

T;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.70

N;N

REVEL

Benign

0.017

Sift

Benign

0.41

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.18

B;B

Vest4

0.43

MVP

0.61

ClinPred

0.0089

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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