16-2116896-C-T

Position:

chr16-2116896-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_001009944.3(PKD1):c.1543G>A(p.Gly515Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G515W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 4.17

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 Pathogenic. Variant got 11 ACMG points.

PM1

In a domain C-type lectin (size 116) in uniprot entity PKD1_HUMAN there are 29 pathogenic changes around while only 4 benign (88%) in NM_001009944.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-2116896-C-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 16-2116896-C-T is Pathogenic according to our data. Variant chr16-2116896-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447972.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=2}. Variant chr16-2116896-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.1543G>A	p.Gly515Arg	missense_variant	7/46	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.1543G>A	p.Gly515Arg	missense_variant	7/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.27e-7

AC:

AN:

1375178

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

680114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.34e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 20, 2020	The PKD1 c.1543G>A; p.Gly515Arg variant (rs1555458704) is reported in the literature in an individual affected with autosomal dominant polycystic kidney disease (Chang 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 515 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another amino acid substitution at this codon (p.Gly515Trp) has been reported in multiple individuals with autosomal dominant polycystic kidney disease, although it has not been conclusively demonstrated to cause disease (Cornec-Le Gall 2013, Kim 2019). Due to limited information, the clinical significance of the p.Gly515Arg variant is uncertain at this time. References: Chang MY et al. Novel PKD1 and PKD2 mutations in Taiwanese patients with autosomal dominant polycystic kidney disease. J Hum Genet. 2013 Nov;58(11):720-7. Cornec-Le Gall E et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013 May;24(6):1006-13. Kim H et al. Genetic Characteristics of Korean Patients with Autosomal Dominant Polycystic Kidney Disease by Targeted Exome Sequencing. Sci Rep. 2019 Nov 18;9(1):16952. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Sep 23, 2022	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 08, 2024

Reported as one of several PKD1 variants (phase unknown) in a patient with polycystic kidney disease in published literature (PMID: 23985799); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on splicing and protein structure/function; This variant is associated with the following publications: (PMID: 23985799) -

PKD1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 30, 2023

The PKD1 c.1543G>A variant is predicted to result in the amino acid substitution p.Gly515Arg. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been reported in an individual with autosomal dominant polycystic kidney disease (ADPKD) (Chang et al. 2013. PubMed ID: 23985799). In addition, we have found this variant in the heterozygous state in multiple presumably unrelated patients tested for cystic kidney disease at PreventionGenetics (internal data). Of note, a different substitution at the same codon define as c.1543G>T (p.Gly515Trp) has been reported in presumably unrelated individuals with polycystic kidney disease (Cornec-Le Gall et al. 2013. PubMed ID: 23431072, Suppl. Table 1; Domingo-Gallego et al. 2021. PubMed ID: 33532864, Suppl. Table 2; Kim et al. 2019. PubMed ID: 31740684, Suppl. Table S6C). This c.1543G>A (p.Gly515Arg) variant is interpreted as pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.6

D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.79

MutPred

0.92

Loss of catalytic residue at W516 (P = 0.0814);Loss of catalytic residue at W516 (P = 0.0814);

MVP

0.83

ClinPred

0.95

GERP RS

4.8

Varity_R

0.26

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.56

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.56

Position offset: -1

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