rs113562492
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_138694.4(PKHD1):c.8521A>G(p.Met2841Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,582,968 control chromosomes in the GnomAD database, including 32 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.8521A>G | p.Met2841Val | missense_variant | 54/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.8521A>G | p.Met2841Val | missense_variant | 54/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.8521A>G | p.Met2841Val | missense_variant | 54/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00654 AC: 993AN: 151936Hom.: 10 Cov.: 32
GnomAD3 exomes AF: 0.00283 AC: 708AN: 249804Hom.: 10 AF XY: 0.00245 AC XY: 331AN XY: 135060
GnomAD4 exome AF: 0.00135 AC: 1933AN: 1430914Hom.: 22 Cov.: 26 AF XY: 0.00126 AC XY: 898AN XY: 713738
GnomAD4 genome ? AF: 0.00657 AC: 999AN: 152054Hom.: 10 Cov.: 32 AF XY: 0.00655 AC XY: 487AN XY: 74330
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Uncertain:1Benign:3
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely benign, criteria provided, single submitter | literature only | Counsyl | Apr 09, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 08, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 30, 2018 | Variant summary: PKHD1 c.8521A>G (p.Met2841Val) located in the G8 domain (via InterPro) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant allele was found at a frequency of 0.0031 in 275668 control chromosomes, predominantly at a frequency of 0.021 within the African subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 3-fold higher than 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 origin. Multiple publications have cited the variant in affected individuals, however, with limited information, i.e. lack of co-occurrence and/or cosegregation data. One publication reports the variant in a compound heterozygote patient, Met2841V/p.Tyr938fs, without providing cosegregation data (Losekoot_2005). Multiple clinical diagnostic laboratories have cited the variant with a classification of "likely benign/benign." Based on the evidence outlined above, the variant was classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 119/13004=0.91%; Frequency in ESP (AA): 103/4303=2.39% - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 20, 2014 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | PKHD1: BP4, BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2020 | This variant is associated with the following publications: (PMID: 22995991, 27884173, 15805161) - |
Polycystic kidney disease Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKHD1 p.Met2841Val variant was identified in 2 of 228 proband chromosomes (frequency: 0.009) from individuals or unrelated families with ARPKD (Losekoot 2005, Sharp 2005). The variant was also identified in the following databases: dbSNP (ID: rs113562492) as “With other allele”, ClinVar (4x, as benign by EGL Genetics, Invitae and likely benign by Counsyl, and Laboratory for Molecular Medicine), LOVD 3.0 (1x, reported "does not affect function") and RWTH AAachen University ARPKD database (1x). The variant was identified in control databases in 856 of 275468 (12 homozygous) chromosomes at a frequency of 0.003 in the following populations: African in 497 (10 homozygous) of 23972 chromosomes (freq. 0.02), other in 17 of 6418 chromosomes (freq. 0.0026), Latino in 37 of 3490 chromosomes (freq. 0.001), European in 49 of 125822 chromosomes (freq. 0.0004), Ashkenazi Jewish in 254 of 10128 chromosomes (freq. 0.025), South Asian in 2 of 30750 chromosomes (freq. 0.000065), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Met2841Val 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 2 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. The variant is located with the G8 domain functional domain(s) increasing the likelihood that it may have clinical significance. In addition the p.Met2841Val variant was identified in trans with the PKHD1 (c.2812_2813del, p.Tyr938fs) mutation (Losekoot 2005). In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at