rs117078377

Positions:

chr4-88008301-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000297.4(PKD2):c.568G>A(p.Ala190Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 1,511,924 control chromosomes in the GnomAD database, including 3,051 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A190A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.030 ( 429 hom., cov: 32)

Exomes 𝑓: 0.025 ( 2622 hom. )

Consequence

PKD2
NM_000297.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.51

Variant links:

Genes affected

PKD2 (HGNC:9009): (polycystin 2, transient receptor potential cation channel) This gene encodes a member of the polycystin protein family. The encoded protein is a multi-pass membrane protein that functions as a calcium permeable cation channel, and is involved in calcium transport and calcium signaling in renal epithelial cells. This protein interacts with polycystin 1, and they may be partners in a common signaling cascade involved in tubular morphogenesis. Mutations in this gene are associated with autosomal dominant polycystic kidney disease type 2. [provided by RefSeq, Mar 2011]

PKD2 links:

(HGNC:):

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=0.002696067).

BP6

Variant 4-88008301-G-A is Benign according to our data. Variant chr4-88008301-G-A is described in ClinVar as [Benign]. Clinvar id is 92796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88008301-G-A is described in Lovd as [Benign]. Variant chr4-88008301-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PKD2	NM_000297.4 linkuse as main transcript	c.568G>A	p.Ala190Thr	missense_variant	1/15	ENST00000237596.7
PKD2	XM_011532028.3 linkuse as main transcript	c.568G>A	p.Ala190Thr	missense_variant	1/14
PKD2	NR_156488.2 linkuse as main transcript	n.667G>A		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD2	ENST00000237596.7 linkuse as main transcript	c.568G>A	p.Ala190Thr	missense_variant	1/15	1	NM_000297.4	P1	Q13563-1
	ENST00000662475.1 linkuse as main transcript	n.112+65C>T		intron_variant, non_coding_transcript_variant
PKD2	ENST00000506727.1 linkuse as main transcript	n.70G>A		non_coding_transcript_exon_variant	1/4	4

Frequencies

GnomAD3 genomes

AF:

0.0298

AC:

4535

AN:

152046

Hom.:

434

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00432

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.0328

Gnomad EAS

AF:

0.384

Gnomad SAS

AF:

0.0842

Gnomad FIN

AF:

0.0636

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.0315

GnomAD3 exomes

AF:

0.0631

AC:

6927

AN:

109856

Hom.:

946

AF XY:

0.0638

AC XY:

3878

AN XY:

60784

show subpopulations

Gnomad AFR exome

AF:

0.00280

Gnomad AMR exome

AF:

0.0246

Gnomad ASJ exome

AF:

0.0367

Gnomad EAS exome

AF:

0.438

Gnomad SAS exome

AF:

0.0725

Gnomad FIN exome

AF:

0.0596

Gnomad NFE exome

AF:

0.0128

Gnomad OTH exome

AF:

0.0413

GnomAD4 exome

AF:

0.0254

AC:

34475

AN:

1359764

Hom.:

2622

Cov.:

AF XY:

0.0268

AC XY:

17982

AN XY:

670572

show subpopulations

Gnomad4 AFR exome

AF:

0.00294

Gnomad4 AMR exome

AF:

0.0247

Gnomad4 ASJ exome

AF:

0.0349

Gnomad4 EAS exome

AF:

0.331

Gnomad4 SAS exome

AF:

0.0727

Gnomad4 FIN exome

AF:

0.0633

Gnomad4 NFE exome

AF:

0.0107

Gnomad4 OTH exome

AF:

0.0404

GnomAD4 genome

AF:

0.0297

AC:

4525

AN:

152160

Hom.:

429

Cov.:

AF XY:

0.0349

AC XY:

2593

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00431

Gnomad4 AMR

AF:

0.0220

Gnomad4 ASJ

AF:

0.0328

Gnomad4 EAS

AF:

0.383

Gnomad4 SAS

AF:

0.0839

Gnomad4 FIN

AF:

0.0636

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.0326

Alfa

AF:

0.0188

Hom.:

Bravo

AF:

0.0279

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0135

AC:

ExAC

AF:

0.0351

AC:

833

Asia WGS

AF:

0.202

AC:

701

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 27, 2019	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The c.568G>A, p.Ala190Thr variant was identified in 6.32% of 645 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

Autosomal dominant polycystic kidney disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is associated with the following publications: (PMID: 17574468, 22008521, 22863349, 18837007, 11438989, 20981092, 15192819, 27894351) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Benign

0.13

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

MutationTaster

Benign

0.014

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.57

REVEL

Benign

0.12

Sift

Benign

0.43

Sift4G

Benign

0.41

Polyphen

0.91

Vest4

0.056

MPC

0.30

ClinPred

0.050

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.32

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