rs146352591

Positions:

chr16-2112358-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.3277C>T(p.His1093Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000763 in 1,587,338 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0047 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 3 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.32

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=0.008589417).

BP6

Variant 16-2112358-G-A is Benign according to our data. Variant chr16-2112358-G-A is described in ClinVar as [Benign]. Clinvar id is 447978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2112358-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00469 (714/152362) while in subpopulation AFR AF= 0.0162 (672/41578). AF 95% confidence interval is 0.0152. There are 6 homozygotes in gnomad4. There are 332 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 714 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.3277C>T	p.His1093Tyr	missense_variant	14/46	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.3277C>T	p.His1093Tyr	missense_variant	14/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00468

AC:

712

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.000743

AC:

166

AN:

223404

Hom.:

AF XY:

0.000550

AC XY:

AN XY:

123602

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.000830

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000101

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000192

Gnomad OTH exome

AF:

0.000524

GnomAD4 exome

AF:

0.000346

AC:

497

AN:

1434976

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

213

AN XY:

714098

show subpopulations

Gnomad4 AFR exome

AF:

0.0120

Gnomad4 AMR exome

AF:

0.000926

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000701

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000181

Gnomad4 OTH exome

AF:

0.000854

GnomAD4 genome

AF:

0.00469

AC:

714

AN:

152362

Hom.:

Cov.:

AF XY:

0.00446

AC XY:

332

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0162

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00185

Hom.:

Bravo

AF:

0.00565

ExAC

AF:

0.000811

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2020	This variant is associated with the following publications: (PMID: 17582161) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 25, 2017

- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 21, 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.His1093Tyr variant was identified in 1 of 404 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Rossetti_2007_17582161). The variant was also identified in dbSNP (ID: rs146352591) as â€šÃ„ÃºNAâ€šÃ„Ã¹, ClinVar (classified benign by Athena Diagnostics Inc), ADPKD Mutation Database (classified likely neutral). The variant was not identified in GeneInsight-COGR, LOVD 3.0, PKD1-LOVD databases. The variant was identified in control databases in 314 of 250392 chromosomes (1 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 278 (1 homozygous) of 19826 chromosomes (freq: 0.01), Other in 2 of 6066 chromosomes (freq: 0.0003), Latino in 27 of 33734 chromosomes (freq: 0.0008), European Non-Finnish in 4 of 118028 chromosomes (freq: 0.00003), and South Asian in 3 of 29860 chromosomes (freq: 0.0001) while not observed in the Ashkenazi Jewish, East Asian and European Finnish populations. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. 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. The p.His1093 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Tyr to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 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

0.18

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.25

T;.

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

T;T

MetaRNN

Benign

0.0086

T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.43

Sift

Benign

0.56

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.74

MVP

0.95

ClinPred

0.036

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.053

gMVP

0.74

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