rs534112936
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM5PP3_ModerateBP6BS2_Supporting
The NM_001009944.3(PKD1):c.8405C>T(p.Pro2802Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,610,336 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2802S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001009944.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.8405C>T | p.Pro2802Leu | missense_variant | 23/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.8405C>T | p.Pro2802Leu | missense_variant | 23/46 | 1 | NM_001009944.3 | P5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152194Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000653 AC: 16AN: 244982Hom.: 0 AF XY: 0.0000895 AC XY: 12AN XY: 134088
GnomAD4 exome AF: 0.0000638 AC: 93AN: 1458024Hom.: 1 Cov.: 34 AF XY: 0.0000896 AC XY: 65AN XY: 725314
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152312Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6AN XY: 74460
ClinVar
Submissions by phenotype
Polycystic kidney disease Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Pro2802Leu variant was identified in 1 of 116 proband chromosomes (frequency: 0.009) from individuals or families with Autosomal Dominant Polycystic Kidney Disease (Rossetti 2003). The variant was also identified in dbSNP (ID: rs534112936) as “NA”. The variant was not found in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, ADPKD Mutation Database, PKD1-LOVD, and PKD1-LOVD 3.0 databases. This variant was identified in the 1000 Genomes Project in 6 of 120,000 chromosomes (frequency: 0.00005) the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 6 of 115124 chromosomes (frequency: 0.00005) of those 5 (0.0003) were South Asian and 1 (0.00001) were European (Non-Finnish), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Pro2802 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 identification of this variant with a co-occurring pathogenic variant increases the likelihood this variant does not have clinical significance. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at