rs55840049

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001009944.3(PKD1):c.4051C>T(p.Arg1351Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00096 in 1,610,818 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1351Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0047 ( 8 hom., cov: 33)

Exomes 𝑓: 0.00057 ( 5 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.667

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011341393).

BP6

Variant 16-2111116-G-A is Benign according to our data. Variant chr16-2111116-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225439.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr16-2111116-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00472 (719/152312) while in subpopulation AFR AF= 0.0163 (679/41570). AF 95% confidence interval is 0.0153. There are 8 homozygotes in gnomad4. There are 348 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 719 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.4051C>T	p.Arg1351Trp	missense_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.4051C>T	p.Arg1351Trp	missense_variant	15/46	1	NM_001009944.3	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00472

AC:

719

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00119

AC:

296

AN:

247814

Hom.:

AF XY:

0.000801

AC XY:

108

AN XY:

134884

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.000754

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00128

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000629

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000567

AC:

827

AN:

1458506

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

361

AN XY:

725606

show subpopulations

Gnomad4 AFR exome

AF:

0.0163

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00300

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000384

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00472

AC:

719

AN:

152312

Hom.:

Cov.:

AF XY:

0.00467

AC XY:

348

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0163

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00207

Hom.:

Bravo

AF:

0.00504

ESP6500AA

AF:

0.0128

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00157

AC:

189

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 09, 2020

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Arg1351Trp variant was identified in 2 of 568 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD (Rossetti_2007, Garcia-Gonzalez_2007). The variant was also identified in dbSNP (ID: rs55840049) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified uncertain significance by Soonchunhyang University Bucheon Hospital), ADPKD Mutation Database (classified likely neutral), and not in COGR, LOVD 3.0, and PKD1-LOVD. The variant was identified in control databases in 466 of 275234 chromosomes (2 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 396 (1 homozygous) of 23852 chromosomes (freq: 0.02), Other in 7 of 6410 chromosomes (freq: 0.001), Latino in 28 of 34396 chromosomes (freq: 0.0008), European Non-Finnish in 10 of 125168 chromosomes (freq: 0.00008), East Asian in 23 (1 homozygous) of 18814 chromosomes (freq: 0.001), and South Asian in 2 of 30768 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish and European Finnish populations. The p.Arg1351 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Trp 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. In addition, the variant was identified in our laboratory in 1 individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.2494dupC, p.Arg832ProfsX40), increasing the likelihood it does not have clinical significance. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2020

This variant is associated with the following publications: (PMID: 22995991, 17574468, 17582161) -

PKD1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2019

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

0.099

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.14

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.83

MVP

0.63

ClinPred

0.025

GERP RS

2.4

Varity_R

0.081

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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