NM_138694.4:c.5125C>G
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_138694.4(PKHD1):c.5125C>G(p.Leu1709Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1709F) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
PKHD1
NM_138694.4 missense
NM_138694.4 missense
Scores
1
10
8
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 6.54
Genes affected
PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a domain IPT/TIG 12; atypical (size 84) in uniprot entity PKHD1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_138694.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-52024685-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.5125C>G | p.Leu1709Val | missense_variant | Exon 32 of 67 | 1 | NM_138694.4 | ENSP00000360158.3 | ||
PKHD1 | ENST00000340994.4 | c.5125C>G | p.Leu1709Val | missense_variant | Exon 32 of 61 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251342Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135836
GnomAD3 exomes
AF:
AC:
1
AN:
251342
Hom.:
AF XY:
AC XY:
1
AN XY:
135836
Gnomad AFR exome
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Gnomad EAS exome
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Gnomad FIN exome
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GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ExAC
AF:
AC:
1
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Uncertain
T;T
Polyphen
D;P
Vest4
MutPred
Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at