rs41273726
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_138694.4(PKHD1):c.3407A>G(p.Tyr1136Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00846 in 1,614,058 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00843 AC: 1282AN: 152124Hom.: 11 Cov.: 32
GnomAD3 exomes AF: 0.00764 AC: 1921AN: 251458Hom.: 26 AF XY: 0.00737 AC XY: 1002AN XY: 135898
GnomAD4 exome AF: 0.00846 AC: 12371AN: 1461816Hom.: 103 Cov.: 31 AF XY: 0.00865 AC XY: 6289AN XY: 727218
GnomAD4 genome AF: 0.00842 AC: 1282AN: 152242Hom.: 11 Cov.: 32 AF XY: 0.00789 AC XY: 587AN XY: 74436
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Uncertain:1Benign:5
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | literature only | Counsyl | Mar 30, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Dec 12, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 28, 2017 | - - |
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 19, 2017 | Variant summary: The PKHD1 c.3407A>G (p.Tyr1136Cys) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not available). This variant was found in 960/121796 control chromosomes (14 homozygotes) at a frequency of 0.007882, which slightly exceeds the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this variant is likely a benign polymorphism. In the literature this variant was reported in multiple patients with ARPKD without strong evidence for causality. One reported patient had co-occurrence of a pathogenic variant PKHD1 c. 1458C>A, p.Tyr486X in cis, supporting the non-pathgoenic nature of the variant of interest (Gunay-Aygun_MGM_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as a likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 06, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | PKHD1: BP4, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 22, 2020 | This variant is associated with the following publications: (PMID: 30343465, 15805161, 21228398) - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 21, 2014 | - - |
Caroli disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory of Molecular Diagnosis of Genetic Disease, Università degli Studi di Napoli Federico II | May 05, 2021 | - - |
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.Tyr1136Cys variant was identified in 1 of 450 proband chromosomes (frequency: 0.002) from individuals or families with ARPKD, and was present in 1 of 400 control chromosomes (frequency: 0.0025) from healthy individuals (Bergmann_2005, Losekoot_2005). The variant was identified in dbSNP (ID: rs41273726) with “other” allele, in the 1000 Genomes Project in 13 of 5000 chromosomes (frequency: 0.0026) and in Exome Variant Server project in 88 of 8600 (frequency 0.01) in European American alleles and 3 of 4406 (frequency 0.0007) African American alleles. The variant was also identified in the Exome Aggregation Consortium database (March 14, 2016) in 959 of 121396 chromosomes of which 14 are homozygotes (frequency 0.0079); or 80 of 6612 European Finnish (frequency 0.0121), 797 of 66734 European non Finnish (frequency 0.01194), 37 of 16512 south Asians (frequency 0.002241), 22 of 11576 Latino (frequency 0.0019), 15 of 10404 African (frequency 0.01442), 1 of 8650 East Asians (frequency 0.0001) and 7 of 908 other (frequency 0.008). The variant was also listed in ClinVar 1x by Emory Genetics Laboratory and 1x by Invitae as benign and identified by Counsyl 1x as likely benign and in Clinvitae by EmyClass 1x as benign. The variant was also identified in RWTH AAachen University ARPKD database with conflicting interpretations: 6x as polymorphism, 11x as pathogenic and 13x as probably pathogenic with control frequency of 0% - 0.5%. The p.Tyr1136 residue is not entirely conserved in mammals and the variant amino acid Cystine is present in frog and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In addition this variant was seen co-occurring with a pathogenic variant (c.8095C>T, p.Gln2699X) in a patient with polycystic kidney disease. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of likely benign. - |
Polycystic kidney disease 4 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at