NM_000297.4(PKD2):c.2398A>C (p.Met800Leu) AND Polycystic kidney disease

Clinical significance:Benign

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001292230.1

Allele description [Variation Report for NM_000297.4(PKD2):c.2398A>C (p.Met800Leu)]

NM_000297.4(PKD2):c.2398A>C (p.Met800Leu)

Gene:
PKD2:polycystin 2, transient receptor potential cation channel [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
4q22.1
Genomic location:
Preferred name:
NM_000297.4(PKD2):c.2398A>C (p.Met800Leu)
HGVS:
  • NC_000004.12:g.88067937A>C
  • NG_008604.1:g.65270A>C
  • NM_000297.4:c.2398A>CMANE SELECT
  • NP_000288.1:p.Met800Leu
  • NC_000004.11:g.88989089A>C
  • NM_000297.3:c.2398A>C
  • NR_156488.2:n.2376A>C
  • Q13563:p.Met800Leu
Protein change:
M800L
Links:
UniProtKB: Q13563#VAR_058829; dbSNP: rs2234917
NCBI 1000 Genomes Browser:
rs2234917
Molecular consequence:
  • NM_000297.4:c.2398A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_156488.2:n.2376A>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Polycystic kidney disease
Synonyms:
Polycystic kidney dysplasia; Enlarged polycystic kidneys; Polycystic kidneys
Identifiers:
MONDO: MONDO:0020642; MedGen: C0022680; OMIM: PS173900; Human Phenotype Ontology: HP:0000113

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001480574Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedBenignunknownclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001480574.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 23, 2021

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