rs772316684
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP3BS2_Supporting
The NM_001009944.3(PKD1):c.997G>A(p.Val333Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,577,832 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 Uncertain significance (★★).
Frequency
Consequence
NM_001009944.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.997G>A | p.Val333Met | missense_variant | Exon 5 of 46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000122 AC: 18AN: 147486Hom.: 1 AF XY: 0.000161 AC XY: 13AN XY: 80938
GnomAD4 exome AF: 0.000160 AC: 228AN: 1425610Hom.: 1 Cov.: 32 AF XY: 0.000137 AC XY: 97AN XY: 710102
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74362
ClinVar
Submissions by phenotype
not specified Uncertain:1
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Polycystic kidney disease, adult type Uncertain:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease (MIM#173900). (I) 0107 - This gene is associated with autosomal dominant disease, with rare reports of biallelic variants causing disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (19 heterozygotes, 1 homozygote). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated PKD domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been described as a VUS in the ClinVar database, and has been reported in one individual with ADPKD in a large cohort study (PMID: 23300259). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
PKD1-related disorder Uncertain:1
The PKD1 c.997G>A variant is predicted to result in the amino acid substitution p.Val333Met. This variant was reported in an individual with polycystic kidney disease (Neumann et al. 2013. PubMed ID: 23300259). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD with one homozygote documented (http://gnomad.broadinstitute.org/variant/16-2167996-C-T). Of note, at this position in mouse is a methionine (Met). Although we suspect this variant may be benign, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at