rs117122807
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_138694.4(PKHD1):c.1877A>G(p.Lys626Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,613,880 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.1877A>G | p.Lys626Arg | missense_variant | 20/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.1877A>G | p.Lys626Arg | missense_variant | 20/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.1877A>G | p.Lys626Arg | missense_variant | 20/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00148 AC: 225AN: 152198Hom.: 6 Cov.: 32
GnomAD3 exomes AF: 0.00284 AC: 713AN: 251288Hom.: 15 AF XY: 0.00262 AC XY: 356AN XY: 135804
GnomAD4 exome AF: 0.00178 AC: 2606AN: 1461564Hom.: 75 Cov.: 30 AF XY: 0.00177 AC XY: 1289AN XY: 727098
GnomAD4 genome ? AF: 0.00146 AC: 223AN: 152316Hom.: 6 Cov.: 32 AF XY: 0.00191 AC XY: 142AN XY: 74484
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Benign:4
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | literature only | Counsyl | Mar 27, 2014 | - - |
Likely 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). 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. - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | May 11, 2017 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | PKHD1: BP4, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2020 | This variant is associated with the following publications: (PMID: 30566001, 28814334, 28578020, 21790888) - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 15, 2015 | - - |
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.Lys626Arg variant was identified in the literature in a case report of a 22 week fetus with findings consistent with ARPKD. Fetal genetic testing was declined, however the father was identified to carry the p.Lys626Arg variant but no additional suspicious variants were identified in the mother or father (Jang 2011). The variant was also identified in dbSNP (ID: rs117122807) “With Benign allele”, ClinVar (classified as benign by Counsyl and Emory Genetics), LOVD 3.0 (unclassified), and the RWTH AAachen University ARPKD database (unclassified) databases, but was not in the Geneinsight-COGR database. The variant was identified in control databases in 734 of 277024 chromosomes (10 homozygous) at a frequency of 0.00265 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Lys626Arg 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; 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 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at