rs76184385

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001009944.3(PKD1):c.8964G>A(p.Ala2988=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00776 in 1,611,016 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0079 ( 65 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.761

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 16-2102618-C-T is Benign according to our data. Variant chr16-2102618-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2102618-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.761 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00637 (970/152370) while in subpopulation EAS AF= 0.00926 (48/5186). AF 95% confidence interval is 0.00717. There are 8 homozygotes in gnomad4. There are 534 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 971 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.8964G>A	p.Ala2988=	synonymous_variant	25/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.8964G>A	p.Ala2988=	synonymous_variant	25/46	1	NM_001009944.3	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00638

AC:

971

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00569

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00923

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0206

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00769

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00748

AC:

1848

AN:

247014

Hom.:

AF XY:

0.00738

AC XY:

995

AN XY:

134770

show subpopulations

Gnomad AFR exome

AF:

0.000521

Gnomad AMR exome

AF:

0.00892

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00985

Gnomad SAS exome

AF:

0.00578

Gnomad FIN exome

AF:

0.0183

Gnomad NFE exome

AF:

0.00660

Gnomad OTH exome

AF:

0.00798

GnomAD4 exome

AF:

0.00791

AC:

11537

AN:

1458646

Hom.:

Cov.:

AF XY:

0.00780

AC XY:

5660

AN XY:

725648

show subpopulations

Gnomad4 AFR exome

AF:

0.00138

Gnomad4 AMR exome

AF:

0.00803

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.0145

Gnomad4 SAS exome

AF:

0.00549

Gnomad4 FIN exome

AF:

0.0186

Gnomad4 NFE exome

AF:

0.00774

Gnomad4 OTH exome

AF:

0.00809

GnomAD4 genome

AF:

0.00637

AC:

970

AN:

152370

Hom.:

Cov.:

AF XY:

0.00717

AC XY:

534

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00568

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00926

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.0206

Gnomad4 NFE

AF:

0.00769

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00607

Hom.:

Bravo

AF:

0.00515

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.00692

EpiControl

AF:

0.00670

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 20, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PKD1: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2021	This variant is associated with the following publications: (PMID: 10854095, 11558899, 12007219, 22383692, 22608885, 24374109) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 25, 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.Ala2988Ala variant was identified in 9 of 1202 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD (Perrichot 2000, Inoue 2002, Mizoguchi 2001, Rossetti 2012, Tan 2012, Tan 2014). The variant was also identified in dbSNP (ID: rs76184385) and ADPKD Mutation Database (as likely neutral). This variant was identified in the 1000 Genomes Project in 31 of 5000 chromosomes (frequency: 0.006), NHLBI GO Exome Sequencing Project in 54 of 8570 European American (freq. 0.006) and in 4 of 4374 of African American alleles (freq. 0.0009).The p.Ala2988Ala variant was also identified in Exome Aggregation Consortium database (March 14, 2016) in 837 (6 homozygous) of 118036 chromosomes (freq. 0.007) in the following populations: European in 412 of 64634 chromosomes (freq. 0.006), Finnish in 120 of 6556 chromosomes (freq. 0.02), Latino in 105 of 11458 chromosomes (freq. 0.009), East Asian in 100 of 8594 chromosomes (freq. 0.01), South Asian in 87 of 16494 chromosomes (freq. 0.005), African in 7 of 9428 chromosomes (freq. 0.0007) and Other in 6 of 872 chromosomes (freq. 0.007), increasing the likelihood this could be a low frequency benign variant. 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.Ala2988Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site.The variant occurs outside of the splicing consensus sequence and 1 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. Two population studies by Perrichot (2000) and Mizoguchi (2001) classified the variant as polymorphism since the variant does not lead to the modification of the encoded amino acid. In addition, another population study by Rossetti (2012) classified the variant as known exonic polymorphic variant. In addition, the variant was identified with a co-occurring pathogenic PKD1 variant in our lab (p.Ala3571_Val3572del), increasing the likelihood that the p.Ala2988Ala variant does not have clinical significance. 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

BayesDel_noAF

Benign

-0.75

Cadd

Benign

2.9

Dann

Benign

0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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