rs7766366
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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.7921A>Gā(p.Thr2641Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,613,126 control chromosomes in the GnomAD database, including 29 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 0.0073 ( 16 hom., cov: 32)
Exomes š: 0.00089 ( 13 hom. )
Consequence
PKHD1
NM_138694.4 missense
NM_138694.4 missense
Scores
1
7
10
Clinical Significance
Conservation
PhyloP100: 3.62
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 (MetaRNN=0.009604186).
BP6
Variant 6-51847961-T-C is Benign according to our data. Variant chr6-51847961-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 96426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51847961-T-C is described in Lovd as [Benign]. Variant chr6-51847961-T-C is described in Lovd as [Likely_pathogenic].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00734 (1117/152208) while in subpopulation AFR AF= 0.0247 (1025/41520). AF 95% confidence interval is 0.0234. There are 16 homozygotes in gnomad4. There are 526 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 16 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.7921A>G | p.Thr2641Ala | missense_variant | 50/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.7921A>G | p.Thr2641Ala | missense_variant | 50/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.7921A>G | p.Thr2641Ala | missense_variant | 50/61 | 5 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00733 AC: 1115AN: 152090Hom.: 16 Cov.: 32
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GnomAD3 exomes AF: 0.00209 AC: 525AN: 251222Hom.: 14 AF XY: 0.00151 AC XY: 205AN XY: 135754
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GnomAD4 exome AF: 0.000886 AC: 1295AN: 1460918Hom.: 13 Cov.: 31 AF XY: 0.000766 AC XY: 557AN XY: 726846
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GnomAD4 genome AF: 0.00734 AC: 1117AN: 152208Hom.: 16 Cov.: 32 AF XY: 0.00707 AC XY: 526AN XY: 74426
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive polycystic kidney disease Benign:5
Likely benign, criteria provided, single submitter | literature only | Counsyl | Mar 27, 2014 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 30, 2017 | - - |
Benign, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Benign, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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 rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 06, 2013 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Oct 01, 2015 | - - |
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 | Mar 15, 2021 | Variant summary: PKHD1 c.7921A>G (p.Thr2641Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251222 control chromosomes, predominantly at a frequency of 0.025 within the African or African-American subpopulation in the gnomAD database, including 12 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.5- fold 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 African or African-American origin. c.7921A>G has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Furu_2003, Melchionda_2016), but also in controls (e.g. Sharp_2005). These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | PKHD1: BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2021 | This variant is associated with the following publications: (PMID: 12874454, 20981092) - |
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.Thr2641Ala variant was identified in 2 of 320 proband chromosomes (frequency: 0.01) from individuals or families with ARPKD and was present in 2 of 200 control chromosomes (frequency: 0.01) from healthy individuals (Furu 2003, Sharp 2005). The variant was also identified in dbSNP (ID: rs7766366) as With other allele, ClinVar (classified as benign by Invitae, Prevention Genetcs, EGL; as likely benign by Counsyl and one clinical laboratory), Clinvitae, LOVD 3.0 (likely pathogenic), RWTH AAachen University ARPKD database (pathogenic), databases. The variant was not identified in GeneInsight-COGR, databases. The variant was identified in control databases in 715 of 276948 chromosomes (14 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 597 of 24022 chromosomes (freq: 0.02), Other in 16 of 6466 chromosomes (freq: 0.002), Latino in 73 of 34392 chromosomes (freq: 0.002), European in 28 of 126528 chromosomes (freq: 0.0002), and South Asian in 1 of 30778 chromosomes (freq: 0.000032), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, populations. The p.Thr2641 residue is conserved in mammals 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Benign
T;T
Sift4G
Pathogenic
D;D
Polyphen
D;P
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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