chr6-51959953-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The ENST00000371117.8(PKHD1):c.5825A>G(p.Asp1942Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000424 in 1,461,330 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 (★★). Synonymous variant affecting the same amino acid position (i.e. D1942D) has been classified as Likely benign.
Frequency
Consequence
ENST00000371117.8 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.5825A>G | p.Asp1942Gly | missense_variant | 36/67 | ENST00000371117.8 | NP_619639.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.5825A>G | p.Asp1942Gly | missense_variant | 36/67 | 1 | NM_138694.4 | ENSP00000360158 | P2 | |
PKHD1 | ENST00000340994.4 | c.5825A>G | p.Asp1942Gly | missense_variant | 36/61 | 5 | ENSP00000341097 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461330Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28AN XY: 726984
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Polycystic kidney disease 4 Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 22, 2021 | - - |
Uncertain significance, flagged submission | clinical testing | Revvity Omics, Revvity | Jun 16, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 16, 2021 | - - |
Autosomal recessive polycystic kidney disease Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 08, 2022 | For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. ClinVar contains an entry for this variant (Variation ID: 434018). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 12846734, 12874454). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1942 of the PKHD1 protein (p.Asp1942Gly). - |
Polycystic kidney disease Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKHD1 p.Asp1942Gly variant was identified in 3 of 560 proband chromosomes (one homozygous individual) (frequency: 0.013) from unrelated Spanish, American and British individuals or families with ARPKD and was not identified in 620 control chromosomes from healthy individuals (Furu 2004, Sharp 2005, Rosetti 2003, Adeva 2006). Furu et al (2004) identified the mutation in an American caucasian individual in which severe perinatal disease led to neonatal death; with the variant co-occurring with another PKHD1 pathogenic mutation (c.1159_1161delAAT, p.Asn387del). Adeva et al (2006) identified the variant in both of the unrelated parents of an affected child who with neonatal demise. A novel protein domain, G8, was identified, that contains 8 conserved glycine residues in which missense variants (p.Asp1942Gly included) reported to be associated with ARPKD disease are localized in (He 2004). The variant was identified in RWTH AAachen University ARPKD database (classification pathogenic) and PKHD1-LOVD (unclassified); and was not identified in dbSNP, Clinvitae database, the ClinVar database, GeneInsight COGR database, 1000 Genomes Project, NHLBI GO Exome Sequencing Project, and the Exome Aggregation Consortium database (March 14, 2016). The p.Asp1942 residue is not conserved across mammals, however 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at