6-51855931-A-G
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_138694.4(PKHD1):āc.7873T>Cā(p.Leu2625=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,614,068 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.00094 ( 1 hom., cov: 33)
Exomes š: 0.0016 ( 47 hom. )
Consequence
PKHD1
NM_138694.4 synonymous
NM_138694.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0230
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 -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 6-51855931-A-G is Benign according to our data. Variant chr6-51855931-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 262415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000939 (143/152332) while in subpopulation SAS AF= 0.0292 (141/4826). AF 95% confidence interval is 0.0253. There are 1 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 47 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.7873T>C | p.Leu2625= | synonymous_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.7873T>C | p.Leu2625= | synonymous_variant | 49/67 | 1 | NM_138694.4 | ENSP00000360158 | P2 | |
PKHD1 | ENST00000340994.4 | c.7873T>C | p.Leu2625= | synonymous_variant | 49/61 | 5 | ENSP00000341097 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000939 AC: 143AN: 152214Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00344 AC: 864AN: 251392Hom.: 15 AF XY: 0.00465 AC XY: 632AN XY: 135866
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GnomAD4 exome AF: 0.00164 AC: 2391AN: 1461736Hom.: 47 Cov.: 30 AF XY: 0.00234 AC XY: 1701AN XY: 727184
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GnomAD4 genome AF: 0.000939 AC: 143AN: 152332Hom.: 1 Cov.: 33 AF XY: 0.00154 AC XY: 115AN XY: 74494
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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:3
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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | May 11, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 12, 2018 | Variant summary: PKHD1 c.7873T>C 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 0.0031 in 277116 control chromosomes, predominantly at a frequency of 0.027 within the South Asian subpopulation in the gnomAD database, including 14 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4-folds higher than 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 South Asian origin. To our knowledge, no occurrence of c.7873T>C in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have 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. - |
Polycystic kidney disease Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKHD1 p.Leu2625= variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs140033417) as "With Likely benign allele", ClinVar (1x likely benign), and the RWTH AAachen University ARPKD database. The variant was also identified in control databases in 867 of 277116 chromosomes (16 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 24026 chromosomes (freq: 0.00008), Other in 13 of 6464 chromosomes (freq: 0.002), Latino in 2 of 34418 chromosomes (freq: 0.00006), European in 8 of 126612 chromosomes (freq: 0.00006), East Asian in 1 of 18870 chromosomes (freq: 0.00005), and South Asian in 841 of 30782 chromosomes (freq: 0.03). The variant was not observed in the Ashkenazi Jewish or Finnish, populations. The p.Leu2625= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 11, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at