chr6-52082389-T-C
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_138694.4(PKHD1):c.281+3A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,614,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 1 hom. )
Consequence
PKHD1
NM_138694.4 splice_donor_region, intron
NM_138694.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9187
2
Clinical Significance
Conservation
PhyloP100: 2.75
Genes affected
PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.58).
BP6
Variant 6-52082389-T-C is Benign according to our data. Variant chr6-52082389-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289883.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.281+3A>G | splice_donor_region_variant, intron_variant | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.281+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_138694.4 | P2 | |||
PKHD1 | ENST00000340994.4 | c.281+3A>G | splice_donor_region_variant, intron_variant | 5 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00104 AC: 159AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000207 AC: 52AN: 251262Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135780
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GnomAD4 exome AF: 0.000103 AC: 150AN: 1461756Hom.: 1 Cov.: 31 AF XY: 0.0000839 AC XY: 61AN XY: 727184
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GnomAD4 genome AF: 0.00104 AC: 159AN: 152300Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63AN XY: 74476
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive polycystic kidney disease Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 14, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 2023 | In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 25, 2016 | - - |
PKHD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 27, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at