rs78361537
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_138694.4(PKHD1):c.7736C>T(p.Ala2579Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000484 in 1,590,508 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_138694.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.7736C>T | p.Ala2579Val | missense_variant, splice_region_variant | 49/67 | ENST00000371117.8 | NP_619639.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.7736C>T | p.Ala2579Val | missense_variant, splice_region_variant | 49/67 | 1 | NM_138694.4 | ENSP00000360158 | P2 | |
PKHD1 | ENST00000340994.4 | c.7736C>T | p.Ala2579Val | missense_variant, splice_region_variant | 49/61 | 5 | ENSP00000341097 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152128Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251254Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135776
GnomAD4 exome AF: 0.0000299 AC: 43AN: 1438262Hom.: 0 Cov.: 29 AF XY: 0.0000237 AC XY: 17AN XY: 717162
GnomAD4 genome AF: 0.000223 AC: 34AN: 152246Hom.: 1 Cov.: 33 AF XY: 0.000255 AC XY: 19AN XY: 74438
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 01, 2021 | This sequence change replaces alanine with valine at codon 2579 of the PKHD1 protein (p.Ala2579Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs78361537, ExAC 0.1%). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 06, 2017 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 26, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 06, 2018 | - - |
PKHD1-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 12, 2024 | The PKHD1 c.7736C>T variant is predicted to result in the amino acid substitution p.Ala2579Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.080% of alleles in individuals of African descent in gnomAD. At this time, 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