rs2234917

chr4-88067937-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M800T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0051 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (33 hom.)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 1.49

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]

ACMG classification

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: {Benign=6, Likely_benign=1, Uncertain_significance=1}. 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. This position pass quality control queck.
• BS2: High AC in GnomAd at 778 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD2	NM_000297.4	c.2398A>C	p.Met800Leu	missense_variant	13/15	ENST00000237596.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD2	ENST00000237596.7	c.2398A>C	p.Met800Leu	missense_variant	13/15	1	NM_000297.4	P1

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 778 AN: 152166 Hom.: 5 Cov.: 32

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.: 6 AF XY: 0.00523 AC XY: 709 AN XY: 135678

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.: 33 Cov.: 32 AF XY: 0.00358 AC XY: 2601 AN XY: 727214

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.: 5 Cov.: 32 AF XY: 0.00516 AC XY: 384 AN XY: 74458

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.: 3

Bravo AF: 0.00536

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00480 AC: 583

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00469

EpiControl AF: 0.00456

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

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	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Polycystic kidney disease 2 Uncertain:1 Benign: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

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

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	Jun 01, 2023	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 “With Benign allele”, 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	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	14
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	D
LIST_S2	Benign	0.76	T;.;T
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.62	N;N;N
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs2234917; hg19: chr4-88989089; COSMIC: COSV52940201;