rs201906247

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138694.4(PKHD1):​c.5410C>T​(p.Arg1804Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1804H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.706
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.01556766).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKHD1NM_138694.4 linkc.5410C>T p.Arg1804Cys missense_variant Exon 34 of 67 ENST00000371117.8 NP_619639.3 P08F94-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKHD1ENST00000371117.8 linkc.5410C>T p.Arg1804Cys missense_variant Exon 34 of 67 1 NM_138694.4 ENSP00000360158.3 P08F94-1
PKHD1ENST00000340994.4 linkc.5410C>T p.Arg1804Cys missense_variant Exon 34 of 61 5 ENSP00000341097.4 P08F94-2

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152094
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00187
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000231
AC:
58
AN:
250692
Hom.:
0
AF XY:
0.000280
AC XY:
38
AN XY:
135516
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.000498
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000784
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000159
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.000196
AC:
286
AN:
1461474
Hom.:
0
Cov.:
32
AF XY:
0.000219
AC XY:
159
AN XY:
727042
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000673
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000168
Gnomad4 OTH exome
AF:
0.000398
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.000175
AC XY:
13
AN XY:
74426
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00187
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000167
Hom.:
0
Bravo
AF:
0.000140
ExAC
AF:
0.000173
AC:
21
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000382
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:2
Nov 05, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1804 of the PKHD1 protein (p.Arg1804Cys). This variant is present in population databases (rs201906247, gnomAD 0.08%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15805161). ClinVar contains an entry for this variant (Variation ID: 501154). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PKHD1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Feb 09, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:2
Apr 05, 2021
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Identified in a patient with ARPKD with a second variant in an unknown phase in published literature (Sharp et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15805161) -

Jun 05, 2018
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

PKHD1-related disorder Uncertain:1
Mar 06, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PKHD1 c.5410C>T variant is predicted to result in the amino acid substitution p.Arg1804Cys. This variant has been reported with a canonical splice variant (c.5381-2A>C) in a fetal specimen due to suspected autosomal recessive polycystic kidney disease (ARPKD) (Sharp et al. 2005. PubMed ID: 15805161). This variant was also described in a large cohort of individuals with suspected early-onset chronic kidney disease (Domingo-Gallego et al. 2022. PubMed ID: 33532864, supplementary data). This variant is reported in 0.078% of alleles in individuals of South Asian descent in gnomAD. This variant could be pathogenic. At this time, however, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Polycystic kidney disease 4 Uncertain:1
Mar 05, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
14
DANN
Uncertain
0.98
DEOGEN2
Benign
0.20
T;.
Eigen
Benign
-0.90
Eigen_PC
Benign
-0.85
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.58
T;T
M_CAP
Benign
0.065
D
MetaRNN
Benign
0.016
T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
0.0
N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-1.2
N;N
REVEL
Benign
0.16
Sift
Benign
0.067
T;T
Sift4G
Benign
0.076
T;T
Polyphen
0.28
B;B
Vest4
0.18
MutPred
0.52
Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP
0.75
MPC
0.15
ClinPred
0.018
T
GERP RS
1.6
Varity_R
0.057
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201906247; hg19: chr6-51882398; COSMIC: COSV61887081; API