chr4-88046767-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000297.4(PKD2):c.1445T>G(p.Phe482Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00218 in 1,611,890 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 12 hom. )

Consequence

PKD2
NM_000297.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 6.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013403147).

BP6

Variant 4-88046767-T-G is Benign according to our data. Variant chr4-88046767-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219481.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5, Likely_benign=2}. Variant chr4-88046767-T-G is described in Lovd as [Likely_benign]. Variant chr4-88046767-T-G is described in Lovd as [Pathogenic]. Variant chr4-88046767-T-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00184 (281/152356) while in subpopulation AMR AF= 0.00255 (39/15304). AF 95% confidence interval is 0.00208. There are 1 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 281 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4 link	c.1445T>G	p.Phe482Cys	missense_variant	Exon 6 of 15	ENST00000237596.7	NP_000288.1	Q13563-1Q9UEU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 link	c.1445T>G	p.Phe482Cys	missense_variant	Exon 6 of 15	1	NM_000297.4	ENSP00000237596.2		Q13563-1
PKD2	ENST00000508588.5 link	c.-199+3310T>G		intron_variant	Intron 1 of 9	2		ENSP00000427131.1		B4DFN3

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

282

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00951

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00204

AC:

513

AN:

251372

Hom.:

AF XY:

0.00202

AC XY:

275

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00972

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00246

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00221

AC:

3225

AN:

1459534

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

1606

AN XY:

726232

show subpopulations

Gnomad4 AFR exome

AF:

0.000658

Gnomad4 AMR exome

AF:

0.00195

Gnomad4 ASJ exome

AF:

0.00950

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.00213

Gnomad4 OTH exome

AF:

0.00343

GnomAD4 genome

AF:

0.00184

AC:

281

AN:

152356

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

127

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00951

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00238

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00267

Hom.:

Bravo

AF:

0.00202

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00212

AC:

257

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00365

EpiControl

AF:

0.00362

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	PKD2: PM5, BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2021	This variant is associated with the following publications: (PMID: 32859249, 18257781, 27894351, 27884173, 18837007, 22995991, 22863349, 31349084) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 04, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease 2

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 07, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD2 p.Phe482Cys variant was identified in 7 of 954 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Bataille 2011, Dedoussis 2008, Edrees 2016, Robinson 2012, Rossetti 2012, Tan 2008). The variant was also identified in the following databases: dbSNP (ID: rs75762896) as With other allele, ClinVar (classified as benign by Invitae; as likely benign by Prevention), Clinvitae , LOVD 3.0, ADPKD Mutation Database (classified as likely neutral). The variant was not identified in the COGR, or PKD1-LOVD databases. The variant was identified in control databases in 548 of 277128 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 7 of 24034 chromosomes (freq: 0.0003), â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 38 of 6462 chromosomes (freq: 0.01), Latino in 67 of 34416 chromosomes (freq: 0.002), EuropeanNon-Finnish in 302 of 126624 chromosomes (freq: 0.002), AshkenaziJewish in 102 of 10152 chromosomes (freq: 0.01), EuropeanFinnish in 3 of 25792 chromosomes (freq: 0.0001), and SouthAsian in 29 of 30782 chromosomes (freq: 0.001); it was not observed in the EastAsian population. The p.Phe482 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) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified with a co-occurring pathogenic PKD1 variant (IVS21â€šÃ„Ã¬2delAG), increasing the likelihood that the p.Phe482Cys variant does not have clinical significance (Dedoussis 2008). 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

REVEL

Benign

0.18

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.012

Polyphen

0.52

Vest4

0.37

MVP

0.28

MPC

0.63

ClinPred

0.031

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.23

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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