rs776866974
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM5PP3_ModerateBS2_Supporting
The NM_001009944.3(PKD1):c.9454C>T(p.Arg3152Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,610,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3152G) 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.9454C>T | p.Arg3152Trp | missense_variant | 27/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.9454C>T | p.Arg3152Trp | missense_variant | 27/46 | 1 | NM_001009944.3 | P5 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000806 AC: 2AN: 248102Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134946
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1458296Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 725482
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74360
ClinVar
Submissions by phenotype
Polycystic kidney disease, adult type Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 02, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 25, 2018 | - - |
PKD1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 28, 2023 | The PKD1 c.9454C>T variant is predicted to result in the amino acid substitution p.Arg3152Trp. This variant was reported in an individual with ciliopathy; the individual also carried a truncating variant in PKD1 (Table 3: patient #52, Vaisitti et al. 2020. PubMed ID: 33226606). This variant is reported in 0.0040% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2150511-G-A). Of note, we have previously found this variant in the heterozygous state with a definitely pathogenic PKD1 variant in two newborns and one fetus with PKD at PreventionGenetics (internal data). Therefore, this variant is highly suspected to be a hypomorphic allele. By itself, it may cause no disease or only relatively mild disease. However, in combination with other pathogenic variants in relevant genes, this type of hypomorphic allele may contribute to disease severity. Therefore, the pathogenicity of the c.9454C>T (p.Arg3152Trp) variant should be considered in the context of an individual’s other genetic findings. At this time, we classify it as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at