rs201210830
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_138694.4(PKHD1):c.12106C>T(p.Arg4036Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,614,124 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4036Q) has been classified as Uncertain significance.
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.12106C>T | p.Arg4036Trp | missense_variant | 67/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.12106C>T | p.Arg4036Trp | missense_variant | 67/67 | 1 | NM_138694.4 | P2 | |
ENST00000589278.6 | n.811-3160G>A | intron_variant, non_coding_transcript_variant | 5 | ||||||
ENST00000454361.1 | n.81-3155G>A | intron_variant, non_coding_transcript_variant | 3 | ||||||
ENST00000650088.1 | n.222-3155G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000722 AC: 11AN: 152260Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000757 AC: 19AN: 250920Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135576
GnomAD4 exome AF: 0.0000978 AC: 143AN: 1461864Hom.: 0 Cov.: 34 AF XY: 0.0000908 AC XY: 66AN XY: 727224
GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152260Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74388
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 13, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | PKHD1: PM2, BP4 - |
Autosomal recessive polycystic kidney disease Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 06, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 09, 2020 | Variant summary: PKHD1 c.12106C>T (p.Arg4036Trp) 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 7.6e-05 in 250920 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (7.6e-05 vs 0.0071), allowing no conclusion about variant significance. However, the variant was also reported in Japanese healthy control databases (HGVD-Kyoto and jMorp) with a frequency of 0.006 (including 1 homozygote in HGVD-Kyoto database). This frequency is somewhat close to the estimated maximal expected allele frequency for a pathogenic PKHD1 variant, therefore this variant might represent a benign polymorphism found primarily in populations of East Asian origin (HGVD). To our knowledge, no occurrence of c.12106C>T in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at