rs143312683

Positions:

chr16-2100066-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The ENST00000262304.9(PKD1):c.9718G>A(p.Ala3240Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,599,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

PKD1
ENST00000262304.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.487

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 -7 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 181) in uniprot entity PKD1_HUMAN there are 63 pathogenic changes around while only 22 benign (74%) in ENST00000262304.9

BP4

Computational evidence support a benign effect (MetaRNN=0.020558327).

BP6

Variant 16-2100066-C-T is Benign according to our data. Variant chr16-2100066-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522080.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chr16-2100066-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.9718G>A	p.Ala3240Thr	missense_variant	29/46	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.9718G>A	p.Ala3240Thr	missense_variant	29/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000403

AC:

AN:

225760

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

123394

show subpopulations

Gnomad AFR exome

AF:

0.000147

Gnomad AMR exome

AF:

0.0000941

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000344

Gnomad FIN exome

AF:

0.000389

Gnomad NFE exome

AF:

0.000758

Gnomad OTH exome

AF:

0.000178

GnomAD4 exome

AF:

0.000518

AC:

750

AN:

1447502

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

387

AN XY:

719352

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.000118

Gnomad4 ASJ exome

AF:

0.000116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000353

Gnomad4 FIN exome

AF:

0.000564

Gnomad4 NFE exome

AF:

0.000620

Gnomad4 OTH exome

AF:

0.000335

GnomAD4 genome

AF:

0.000427

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000470

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000975

Hom.:

Bravo

AF:

0.000329

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000935

AC:

ExAC

AF:

0.000442

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2021

The c.9718G>A (p.A3240T) alteration is located in exon 29 (coding exon 29) of the PKD1 gene. This alteration results from a G to A substitution at nucleotide position 9718, causing the alanine (A) at amino acid position 3240 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Polycystic kidney disease

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ala3240Thr variant was identified in 2 of 572 proband chromosomes (frequency: 0.003) from Czech and American individuals or families with ADPKD (Obeidova 2014, Rossetti 2012). The variant was also identified in dbSNP (ID: rs143312683) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified as uncertain significance by Ambry Genetics), and ADPKD Mutation Database (classified as likely neutral). The variant was not identified in the LOVD 3.0 and PKD1-LOVD databases. The variant was identified in control databases in 119 of 252510 chromosomes at a frequency of 0.0005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 21586 chromosomes (freq: 0.0001), Latino in 3 of 31912 chromosomes (freq: 0.00009), European Non-Finnish in 101 of 112472 chromosomes (freq: 0.0009), Ashkenazi Jewish in 1 of 9600 chromosomes (freq: 0.0001), European Finnish in 10 of 24550 chromosomes (freq: 0.0004), and South Asian in 1 of 29260 chromosomes (freq: 0.00003), while it was not observed in the Other or East Asian 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 p.Ala3240 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Thr variant impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 30, 2020

- -

PKD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 07, 2023

This variant is classified as likely 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

0.076

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.078

Sift

Benign

0.29

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.58

P;B

Vest4

0.25

MVP

0.62

ClinPred

0.011

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.022

gMVP

0.17

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