rs141622697
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_138694.4(PKHD1):c.2243C>T(p.Ala748Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A748A) has been classified as Likely benign.
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.2243C>T | p.Ala748Val | missense_variant | 22/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.2243C>T | p.Ala748Val | missense_variant | 22/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.2243C>T | p.Ala748Val | missense_variant | 22/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000559 AC: 85AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251134Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135722
GnomAD4 exome AF: 0.0000794 AC: 116AN: 1461802Hom.: 0 Cov.: 34 AF XY: 0.0000798 AC XY: 58AN XY: 727214
GnomAD4 genome ? AF: 0.000558 AC: 85AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34AN XY: 74488
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 29, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2022 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Autosomal recessive polycystic kidney disease Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 26, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 20, 2019 | Variant summary: PKHD1 c.2243C>T (p.Ala748Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 282530 control chromosomes, predominantly at a frequency of 0.0022 within the African subpopulation in the gnomAD database. This frequency is not higher than the expected maximum for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (0.0022 vs 0.0071), allowing no conclusion about variant significance. c.2243C>T has been reported in the literature in an individual affected with transitional cell carcinoma, but is unclear whether it was a germline or somatic occurrence. This report does 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. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
PKHD1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 30, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at