rs17752991
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_138694.4(PKHD1):c.9492C>T(p.Ser3164Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,613,830 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00090 ( 4 hom. )
Consequence
PKHD1
NM_138694.4 synonymous
NM_138694.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.39
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 Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 6-51748124-G-A is Benign according to our data. Variant chr6-51748124-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 96443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51748124-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.39 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00108 (165/152262) while in subpopulation EAS AF= 0.0201 (104/5180). AF 95% confidence interval is 0.017. There are 0 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.9492C>T | p.Ser3164Ser | synonymous_variant | 58/67 | ENST00000371117.8 | NP_619639.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.9492C>T | p.Ser3164Ser | synonymous_variant | 58/67 | 1 | NM_138694.4 | ENSP00000360158.3 | ||
PKHD1 | ENST00000340994.4 | c.9492C>T | p.Ser3164Ser | synonymous_variant | 58/61 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes AF: 0.00108 AC: 164AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00182 AC: 457AN: 250854Hom.: 2 AF XY: 0.00173 AC XY: 234AN XY: 135528
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GnomAD4 exome AF: 0.000904 AC: 1321AN: 1461568Hom.: 4 Cov.: 33 AF XY: 0.000871 AC XY: 633AN XY: 727126
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GnomAD4 genome AF: 0.00108 AC: 165AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99AN XY: 74448
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive polycystic kidney disease Benign:4
Likely benign, criteria provided, single submitter | literature only | Counsyl | Aug 14, 2014 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | May 11, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 09, 2012 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 15, 2019 | Variant summary: PKHD1 c.9492C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0018 in 282262 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.018 in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Moreover, the variant was also reported in Japanese healthy controls with a frequency of 0.0256 (including 2 homozygotes) that is approximately 3.6-fold higher than the estimated maximal expected allele frequency for a pathogenic PKHD1 variant, further supporting that the variant is a benign polymorphism found primarily in populations of East Asian origin (HGVD). c.9492C>T has also been reported in the literature in healthy control individuals (e.g. Furu 2003, Bergmann 2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 23, 2021 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at