rs2234917

Positions:

chr4-88067937-A-C

Variant summary

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

The NM_000297.4(PKD2):c.2398A>C(p.Met800Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,614,092 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0051 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 33 hom. )

Consequence

PKD2
NM_000297.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.49

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:

PKD2 (HGNC:):

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=0.0069056153).

BP6

Variant 4-88067937-A-C is Benign according to our data. Variant chr4-88067937-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219985.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=6}. Variant chr4-88067937-A-C is described in Lovd as [Benign]. Variant chr4-88067937-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00511 (778/152282) while in subpopulation SAS AF= 0.0118 (57/4828). AF 95% confidence interval is 0.00936. There are 5 homozygotes in gnomad4. There are 384 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 778 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4 linkuse as main transcript	c.2398A>C	p.Met800Leu	missense_variant	13/15	ENST00000237596.7	NP_000288.1	Q13563-1Q9UEU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 linkuse as main transcript	c.2398A>C	p.Met800Leu	missense_variant	13/15	1	NM_000297.4	ENSP00000237596.2		Q13563-1

Frequencies

GnomAD3 genomes

AF:

0.00511

AC:

778

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00717

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00655

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0120

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.00292

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00487

AC:

1222

AN:

251060

Hom.:

AF XY:

0.00523

AC XY:

709

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.00806

Gnomad AMR exome

AF:

0.00402

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0117

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00293

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00316

AC:

4625

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00358

AC XY:

2601

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00774

Gnomad4 AMR exome

AF:

0.00427

Gnomad4 ASJ exome

AF:

0.0205

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0114

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.00197

Gnomad4 OTH exome

AF:

0.00566

GnomAD4 genome

AF:

0.00511

AC:

778

AN:

152282

Hom.:

Cov.:

AF XY:

0.00516

AC XY:

384

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00717

Gnomad4 AMR

AF:

0.00654

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0118

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00293

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00406

Hom.:

Bravo

AF:

0.00536

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00480

AC:

583

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00456

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	May 06, 2022	- -

Polycystic kidney disease 2

Uncertain:1Benign:1

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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 27, 2020	- -

Autosomal dominant polycystic kidney disease

Benign:2

Likely benign, criteria provided, single submitter	research	Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2020	This variant is associated with the following publications: (PMID: 17574468, 11968093, 27884173, 27535533, 27894351, 19936001) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PKD2: BP4, BS1, BS2 -

Joubert syndrome 7

Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Met800Leu variant in PKD2 has been identified in 3 individuals with polycystic kidney disease, segregated with disease in 3 individuals from 1 family (PMID: 19936001), and has been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant polycystic kidney disease. -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD2 p.Met800Leu variant was identified in 4 of 688 proband chromosomes (frequency: 0.006) from Spanish, Czech, American individuals or families with ADPKD (Gomez 2009, Reiterova 2002, Garcia-Gonzalez 2007, Rossetti 2012). Gomez et al (2009) identified the variant in a male proband and his two sisters all with terminal chronic kidney disease in their 50s, the variant was not present in his healthy daughters, however genetic testing of PKD1 was not performed in this family which would have been appropriate considering the severity of the phenotype. Reiterova et al (2002) identified the variant in a family with a generally mild course of disease (ESRD not before 65 years), the variant did not segregate with disease and co-occurred with a PKD2 frameshift variant (1339-1345INSGCAACAG, frameshift 448-472X). In addition the variant was identified in a family with ADPKD and was considered a polymorphism as it did not segregate with disease (Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs2234917) as â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, Clinvitae (classification benign), ClinVar (classification benign, submitters Invitae and Prevention Genetics), ADPKD Mutation Database (classification likely neutral); and was not in GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was identified in the 1000 Genomes Project in 29 of 5000 chromosomes (frequency: 0.006), HAPMAP-SAS in 10 of 978 chromosomes (frequency: 0.01), HAPMAP-AFR in 12 of 1322 chromosomes (frequency: 0.009), HAPMAP-AMR in 4 of 694 chromosomes (frequency: 0.006), the NHLBI GO Exome Sequencing Project in 24 of 8600 European American (frequency: 0.0028) and in 24 of 8600 African American alleles (frequency: 0.0075), and in the Exome Aggregation Consortium database (August 8th 2016) in 583 (4 homozygous) of 121146 chromosomes (freq. 0.005) in the following populations: South Asian in 193 of 16502 chromosomes (freq. 01), African in 86 of 10404 chromosomes (freq. 0.008), Other in 5 of 902 chromosomes (freq. 0.006), European (Non-Finnish) in 264 of 66630 chromosomes (freq. 004), and Latino in 29 of 11528 chromosomes (freq. 0.003), EFinnish in 6 of 6602 chromosomes (frequency: 0.0009), but was not seen in East Asian population, increasing the likelihood this could be a low frequency benign variant; however, we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Met800 residue is not conserved in mammals and and the variant amino acid Leucine is present in dog and chicken, increasing the likelihood that this variant does not have clinical significance. 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 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. 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

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.14

T;T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

T;.;T

MetaRNN

Benign

0.0069

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

L;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.11

N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.67

T;T;T

Sift4G

Benign

0.94

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.25

MutPred

0.49

Gain of glycosylation at S804 (P = 2e-04);.;.;

MVP

0.95

MPC

0.14

ClinPred

0.0022

GERP RS

3.1

Varity_R

0.046

gMVP

0.13

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