chr16-2091460-C-T

Position:

chr16-2091460-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BS1_SupportingBS2

The NM_001009944.3(PKD1):c.11675G>A(p.Arg3892His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000664 in 1,260,028 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00070 ( 3 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 2.33

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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

PKD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a topological_domain Extracellular (size 214) in uniprot entity PKD1_HUMAN there are 39 pathogenic changes around while only 11 benign (78%) in NM_001009944.3

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000704 (783/1111580) while in subpopulation NFE AF= 0.000795 (744/935436). AF 95% confidence interval is 0.000748. There are 3 homozygotes in gnomad4_exome. There are 383 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.11675G>A	p.Arg3892His	missense_variant	42/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.11675G>A	p.Arg3892His	missense_variant	42/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.000364

AC:

AN:

148448

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000977

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000605

Gnomad ASJ

AF:

0.000293

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000585

Gnomad OTH

AF:

0.000491

GnomAD3 exomes

AF:

0.000768

AC:

AN:

10416

Hom.:

AF XY:

0.000866

AC XY:

AN XY:

6928

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:

0.00

Gnomad NFE exome

AF:

0.00164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000704

AC:

783

AN:

1111580

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

383

AN XY:

538142

show subpopulations

Gnomad4 AFR exome

AF:

0.0000994

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.000313

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000395

Gnomad4 NFE exome

AF:

0.000795

Gnomad4 OTH exome

AF:

0.000723

GnomAD4 genome

AF:

0.000364

AC:

AN:

148448

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

72264

show subpopulations

Gnomad4 AFR

AF:

0.0000977

Gnomad4 AMR

AF:

0.000605

Gnomad4 ASJ

AF:

0.000293

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000585

Gnomad4 OTH

AF:

0.000491

Alfa

AF:

0.000641

Hom.:

Bravo

AF:

0.000393

ExAC

AF:

0.000229

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Jul 24, 2023	This sequence variant is a single nucleotide substitution (G>A) at position 11675 of the coding sequence of the PKD1 gene that results in an arginine to histidine amino acid change at residue 3892 of the PKD1 protein. This is a previously reported variant (ClinVar 1256435) that has been observed as heterozygous or compound heterozygous in individuals with polycystic kidney disease (PMID: 33168999, 26139440, 23300259). This variant is present in 17 of 37712 alleles (0.0451%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this arginine to histidine amino acid change would be damaging, and the Arg3892 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 27, 2022	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 09, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 03, 2024	BS1, PP3, PS4_moderate -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 14, 2022

Variant summary: PKD1 c.11675G>A (p.Arg3892His) results in a non-conservative amino acid change located in the Polycystin cation channel (PKD1/PKD2) domain (IPR013122) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 (54 heterozygotes) in 147232 control chromosomes (gnomAD v3.1, genomes dataset). The high number of heterozygous carriers argues against a fully penetrant autosomal dominant disease association for the variant. The variant, c.11675G>A, has been reported in the literature in at least two adult individuals affected with polycystic kidney disease, however without supportive evidence for causality (Neumann_2013, Audrezet_2016). In addition, the variant was also reported in early onset polycystic kidney disease, together with other variants, therefore the authors of this study proposed hypomorphic role for this variant, with a potential biallelic or digenic inheritance (Durkie_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

PKD1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2024

The PKD1 c.11675G>A variant is predicted to result in the amino acid substitution p.Arg3892His. This variant was previously reported in one patient with polycystic kidney disease (PKD), but no functional or genetic studies were performed to help assess the pathogenicity of this variant (Neumann et al. 2013. PubMed ID: 23300259). This variant along with a truncating variant in the PKD2 gene was reported in one case with very early onset PKD; and in the second case with very early onset PKD, this variant was reported in the compound heterozygous state with another PKD1 variant, suggesting this variant could be a hypomorphic allele. By itself, this type of variant may cause no disease or only relatively mild disease. However, in combination with other pathogenic variants, it may contribute to disease severity (Durkie et al. 2021. PubMed ID: 33168999). This variant is reported in 0.096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.61

D;D

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.9

N;N

REVEL

Pathogenic

0.83

Sift

Benign

0.14

T;T

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;D

Vest4

0.39

MutPred

0.66

Loss of sheet (P = 0.0457);.;

MVP

0.94

ClinPred

0.29

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.39

gMVP

0.54

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