chr6-52010452-A-C
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_138694.4(PKHD1):c.5608T>G(p.Leu1870Val) variant causes a missense change. The variant allele was found at a frequency of 0.993 in 1,597,222 control chromosomes in the GnomAD database, including 787,696 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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 |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.5608T>G | p.Leu1870Val | missense_variant | Exon 35 of 67 | 1 | NM_138694.4 | ENSP00000360158.3 | ||
PKHD1 | ENST00000340994.4 | c.5608T>G | p.Leu1870Val | missense_variant | Exon 35 of 61 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes AF: 0.961 AC: 146193AN: 152086Hom.: 70555 Cov.: 30
GnomAD3 exomes AF: 0.990 AC: 248675AN: 251296Hom.: 123198 AF XY: 0.993 AC XY: 134829AN XY: 135816
GnomAD4 exome AF: 0.996 AC: 1439260AN: 1445018Hom.: 717097 Cov.: 31 AF XY: 0.997 AC XY: 717668AN XY: 720126
GnomAD4 genome AF: 0.961 AC: 146293AN: 152204Hom.: 70599 Cov.: 30 AF XY: 0.963 AC XY: 71696AN XY: 74416
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Benign:4
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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not specified Benign:2
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Polycystic kidney disease 4 Benign:2
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Polycystic kidney disease Benign:1
The PKHD1 p.Leu1870Val variant was identified in RWTH AAachen University ARPKD database as a polymorphism, noting the variant is c.5608G>T (current reference base T), p.Val1870Leu (current reference amino acid Leu), and in control databases in 3683 of 277008 chromosomes at a frequency of 0.0133 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 3337 of 24020 chromosomes (freq: 0.1389), Other in 38 of 6468 chromosomes (freq: .0059), Latino in 234 of 34402 chromosomes (freq: .0068), European Non-Finnish in 56 of 126528 chromosomes (freq: .0004), Ashkenazi Jewish in 10 of 10148 chromosomes (freq: .001), East Asian in 1 of 18868 chromosomes (freq: 0.0001), and South Asian in 7 of 30782 chromosomes (freq: 0.0002), while not observed in the European Finnish population. The previously recognized PKHD1 p.Leu1870Val variant was identified dbSNP (ID: rs2435322) “With Benign allele”, ClinVar (classified benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Prevention Genetics, Illumina), Clinvitae (3x), and was not identified in the literature or LOVD 3.0. The previously recognized p.Leu1870 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of Val impacting the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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 this variant meets our laboratory criteria to be classified as benign. -
not provided Benign:1
This variant is associated with the following publications: (PMID: 28509106) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at