rs13333553

Positions:

chr16-2103413-A-T

Variant summary

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

The NM_001009944.3(PKD1):c.8644T>A(p.Trp2882Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 1,599,366 control chromosomes in the GnomAD database, including 1,050 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 0.047 ( 553 hom., cov: 31)

Exomes 𝑓: 0.0048 ( 497 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.124

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 (HGNC:):

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=0.0021344721).

BP6

Variant 16-2103413-A-T is Benign according to our data. Variant chr16-2103413-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 257025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2103413-A-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 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.8644T>A	p.Trp2882Arg	missense_variant	23/46	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.8644T>A	p.Trp2882Arg	missense_variant	23/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0469

AC:

7130

AN:

152152

Hom.:

553

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0219

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.0363

GnomAD3 exomes

AF:

0.0118

AC:

2759

AN:

233310

Hom.:

212

AF XY:

0.00872

AC XY:

1127

AN XY:

129210

show subpopulations

Gnomad AFR exome

AF:

0.168

Gnomad AMR exome

AF:

0.00896

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000394

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000390

Gnomad OTH exome

AF:

0.00409

GnomAD4 exome

AF:

0.00476

AC:

6894

AN:

1447096

Hom.:

497

Cov.:

AF XY:

0.00396

AC XY:

2853

AN XY:

720446

show subpopulations

Gnomad4 AFR exome

AF:

0.163

Gnomad4 AMR exome

AF:

0.0103

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000418

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000247

Gnomad4 OTH exome

AF:

0.0110

GnomAD4 genome

AF:

0.0469

AC:

7139

AN:

152270

Hom.:

553

Cov.:

AF XY:

0.0450

AC XY:

3350

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.161

Gnomad4 AMR

AF:

0.0218

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.0360

Alfa

AF:

0.0190

Hom.:

Bravo

AF:

0.0536

ESP6500AA

AF:

0.130

AC:

515

ESP6500EA

AF:

0.000770

AC:

ExAC

AF:

0.0137

AC:

1602

Asia WGS

AF:

0.00895

AC:

AN:

3476

EpiCase

AF:

0.000164

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2019	This variant is associated with the following publications: (PMID: 17574468, 17582161, 22008521) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 17, 2019

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Trp2882Arg variant is identified in the literature in 3 of 716 proband chromosomes (frequency: 0.004) as a polymorphism from individuals or families with ADPKD, but it was not identified in 442 control chromosomes from healthy individuals (Bataille 2011, Rossetti 2007, Garcia-Gonzalez 2007). In addition the PKD1 p.Glu2966Asp variant was reported as co-occurring with 2 pathogenic PKD1 variants (1470A>G, Y420C and 4262C>T, R1351W) in a proband (Garcia-Gonzalez_2007). The variant was also identified in dbSNP (ID: rs13333553) as â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, Clinvitae (as benign), ClinVar (as benign, by Prevention Genetics), ADPKD Mutation Database (as likely neutral). This variant was identified in the 1000 Genomes Project in 254 of 5008 chromosomes (frequency: 0.050), the NHLBI GO Exome Sequencing Project in 6 of 7794 European American alleles (freq: 0.0007) and in 515 of 3964 African American alleles (freq: 0.13), the genome Aggregation Database (beta, October 19th 2016) in 3124 (239 homozygous) of 236960 chromosomes (freq. 0.013), the Exome Aggregation Consortium database (August 8th 2016) in 1510 (122 homozygous) of 112386 chromosomes (freq. 0.013) in the following populations: African in 1403 of 8206 chromosomes (freq. 0.171), Latino in 80 of 11338 chromosomes (freq. 0.007), other in 5 of 832 chromosomes (freq. 0.006), South Asian in 6 of 16338 chromosomes (freq. 0.0003), and European in 16 of 60860 chromosomes (freq. 0.0002), but was not seen in East Asian and Finnish populations. The variant was identified by our laboratory in 2 individuals with ADPKD, co-occurring with a pathogenic PKD1 variant (c.3489delC, p.Phe1163Leufsx8 and c.2494dupC, p.Arg832ProfsX40), increasing the likelihood that the p.Trp2882Arg variant does not have clinical significance. The p.Trp2882Arg variant was not identified in the PKD1-LOVD, PKD1-LOVD 3.0, COGR and HAPMAP databases. The p.Trp2882 residue is not conserved in mammals and other organisms and four out of five 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. -

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

0.082

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.1

DANN

Benign

0.46

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.29

T;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.83

N;N

REVEL

Benign

0.076

Sift

Benign

0.37

T;T

Sift4G

Benign

0.46

T;T

Polyphen

0.054

B;B

Vest4

0.10

MutPred

0.46

Gain of disorder (P = 0.0026);Gain of disorder (P = 0.0026);

ClinPred

0.00031

GERP RS

2.6

Varity_R

0.034

gMVP

0.55

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