chr6-51772738-G-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_138694.4(PKHD1):c.8606C>A(p.Thr2869Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0117 in 1,597,930 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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PKHD1 | ENST00000371117.8 | c.8606C>A | p.Thr2869Lys | missense_variant | Exon 55 of 67 | 1 | NM_138694.4 | ENSP00000360158.3 | ||
PKHD1 | ENST00000340994.4 | c.8606C>A | p.Thr2869Lys | missense_variant | Exon 55 of 61 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes AF: 0.0102 AC: 1547AN: 151846Hom.: 11 Cov.: 31
GnomAD3 exomes AF: 0.00927 AC: 2325AN: 250704Hom.: 21 AF XY: 0.00908 AC XY: 1230AN XY: 135496
GnomAD4 exome AF: 0.0118 AC: 17087AN: 1445966Hom.: 152 Cov.: 26 AF XY: 0.0118 AC XY: 8535AN XY: 720306
GnomAD4 genome AF: 0.0102 AC: 1548AN: 151964Hom.: 11 Cov.: 31 AF XY: 0.00948 AC XY: 704AN XY: 74232
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Benign:5
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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. -
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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. -
not provided Benign:4
PKHD1: BS1, BS2 -
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This variant is associated with the following publications: (PMID: 12874454, 15108277, 15805161, 15698423, 28492530, 12846734, 16133180, 25701400) -
Variant summary: c.8606C>A affects a conserved nucleotide, resulting in amino acid change from Thr to Lys. 3/4 in-silico tools predict this variant to be damaging, however, these in silico predictions have not been validated by any in vitro/vivo functional studies yet. This variant was found in 1133/121106 control chromosomes at a frequency of 0.0093554, predominantly observed in non-Finnish European subpopulation in ExAC with MAF of 0.01445 (962/66572 chr) with total 14 homozygotes. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0070711), suggesting this variant is a benign polymorphism in non-Finnish Europeans. Two clinical laboratories via ClinVar classified this variant as benign/likely benign. Autosomal Recessive Polycystic Kidney Disease database and multiple literature publications list this variant as polymorphism. Considering all, this variant was classified as Likely Benign until more information becomes available. -
not specified Benign:2
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Polycystic kidney disease Benign:1
The PKHD1 p.Thr2869Lys variant was identified in 5 of 122 proband chromosomes (frequency: 0.041) from Spanish, American and British individuals or families with ARPKD/congenital hepatic fibrosis/Caroli’s disease, and was present in 5 of 420 control chromosomes (frequency: 0.012) from healthy individuals (Rosetti 2003, Furu 2004, Sharp 2005). Kindreds in which the variant was identified also carried multiple other variants, with at least one being pathogenic (Rosetti 2003). The variant was also identified in dbSNP (ID: rs142522748) “With likely benign allele”, Clinvitae database (classifications benign/likely benign), the ClinVar database (classification benign by Emory Genetics Laboratory, and likely benign by Counsyl), RWTH AAachen University ARPKD database (classified as a polymorphism) and PKHD1-LOVD (not classified); in the 1000 Genomes Project in 21 of 5000 chromosomes (frequency: 0.0042), HAPMAP populations EUR in 9 of 1006 chromosomes (frequency: 0.0089) and AMR in 12 of 694 chromosomes (frequency: 0.0173), NHLBI GO Exome Sequencing Project in 115 of 8600 European American alleles (frequency: 0.0134) and in 8 of 4406 African American alleles (frequency: 0.0018), and in the Exome Aggregation Consortium database (March 14, 2016) in 976 of 66572 chromosomes (frequency: 0.0145) from a population of European (Non-Finnish) individuals, and none in the East Asian, Other, African, Latino, South Asian, or European (Finnish) populations. The p.Thr2869 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as likely benign. -
Caroli disease Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at