chr6-51746842-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_Moderate
The NM_138694.4(PKHD1):c.9877G>A(p.Asp3293Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,610,780 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3293V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.9877G>A | p.Asp3293Asn | missense_variant | 59/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.9877G>A | p.Asp3293Asn | missense_variant | 59/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.9877G>A | p.Asp3293Asn | missense_variant | 59/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152054Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458726Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 725876
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152054Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74278
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 3293 of the PKHD1 protein (p.Asp3293Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PKHD1-related disease (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406892). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. This variant disrupts the p.Asp3293 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12506140, 12874454, 15698423). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at