rs200509641

Positions:

chr16-2104548-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.8111C>T(p.Ala2704Val) variant causes a missense change. The variant allele was found at a frequency of 0.000896 in 1,589,016 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00092 ( 10 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.06

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=0.008843273).

BP6

Variant 16-2104548-G-A is Benign according to our data. Variant chr16-2104548-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 440103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2104548-G-A is described in Lovd as [Likely_benign]. Variant chr16-2104548-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00092 (1324/1439004) while in subpopulation MID AF= 0.0095 (39/4106). AF 95% confidence interval is 0.00714. There are 10 homozygotes in gnomad4_exome. There are 806 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.8111C>T	p.Ala2704Val	missense_variant	22/46	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.8111C>T	p.Ala2704Val	missense_variant	22/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.000660

AC:

AN:

149894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000347

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000530

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000202

Gnomad SAS

AF:

0.00318

Gnomad FIN

AF:

0.00171

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000548

Gnomad OTH

AF:

0.000969

GnomAD3 exomes

AF:

0.00142

AC:

223

AN:

156602

Hom.:

AF XY:

0.00177

AC XY:

150

AN XY:

84578

show subpopulations

Gnomad AFR exome

AF:

0.000121

Gnomad AMR exome

AF:

0.000274

Gnomad ASJ exome

AF:

0.000355

Gnomad EAS exome

AF:

0.000324

Gnomad SAS exome

AF:

0.00531

Gnomad FIN exome

AF:

0.000809

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.00204

GnomAD4 exome

AF:

0.000920

AC:

1324

AN:

1439004

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

806

AN XY:

714798

show subpopulations

Gnomad4 AFR exome

AF:

0.000423

Gnomad4 AMR exome

AF:

0.000442

Gnomad4 ASJ exome

AF:

0.000233

Gnomad4 EAS exome

AF:

0.000408

Gnomad4 SAS exome

AF:

0.00538

Gnomad4 FIN exome

AF:

0.00166

Gnomad4 NFE exome

AF:

0.000546

Gnomad4 OTH exome

AF:

0.00163

GnomAD4 genome

AF:

0.000660

AC:

AN:

150012

Hom.:

Cov.:

AF XY:

0.000710

AC XY:

AN XY:

73196

show subpopulations

Gnomad4 AFR

AF:

0.000346

Gnomad4 AMR

AF:

0.000529

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000202

Gnomad4 SAS

AF:

0.00319

Gnomad4 FIN

AF:

0.00171

Gnomad4 NFE

AF:

0.000548

Gnomad4 OTH

AF:

0.000959

Alfa

AF:

0.000849

Hom.:

Bravo

AF:

0.000635

ESP6500AA

AF:

0.000242

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.000895

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 08, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	PKD1: BP4, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 02, 2016

- -

Polycystic kidney disease, adult type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 02, 2021

- -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ala2704Val variant was identified in 1 of 74 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Bataille 2011). The variant was also identified in dbSNP (ID: rs200509641), LOVD 3.0 (2X), and the ADPKD Mutation Database (likely neutral). The variant was not identified in ClinVar, COGR, or PKD1-LOVD databases. The variant was identified in control databases in 239 of 180276 chromosomes at a frequency of 0.001 in the following populations: South Asian in 125 of 23404 chromosomes (freq. 0.005), European in 70 of 73288 chromosomes (freq. 0.001), Finnish in 19 of 15662 chromosomes (freq. 0.001), Other in 8 of 4820 chromosomes (freq. 0.002), Latino in 7 of 25668 chromosomes (freq. 0.0003), East Asian in 4 of 13122 chromosomes (freq.0.0003), African in 3 of 15856 chromosomes (freq. 0.0002), Ashkenazi Jewish in 3 of 8466 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. This variant was also identified in one individual from our laboratory with a co-occurring pathogenic variant in PKD2 (c.1704dupT, p.Val569CysfsX4), increasing the likelihood this variant does not have clinical significance. The p.Ala2704 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Likely benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.80

T;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.12

Sift

Benign

0.081

T;T

Sift4G

Benign

0.088

T;T

Polyphen

0.60

P;P

Vest4

0.056

MVP

0.49

ClinPred

0.020

GERP RS

-0.39

Varity_R

0.027

gMVP

0.15

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