rs786204529

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_138694.4(PKHD1):​c.2279G>A​(p.Arg760His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000112 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R760W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 missense, splice_region

Scores

1
6
12
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 4.89
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 Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-52050157-C-T is Pathogenic according to our data. Variant chr6-52050157-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52050157-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PKHD1NM_138694.4 linkuse as main transcriptc.2279G>A p.Arg760His missense_variant, splice_region_variant 22/67 ENST00000371117.8 NP_619639.3 P08F94-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PKHD1ENST00000371117.8 linkuse as main transcriptc.2279G>A p.Arg760His missense_variant, splice_region_variant 22/671 NM_138694.4 ENSP00000360158.3 P08F94-1
PKHD1ENST00000340994.4 linkuse as main transcriptc.2279G>A p.Arg760His missense_variant, splice_region_variant 22/615 ENSP00000341097.4 P08F94-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251138
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135728
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461670
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727124
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152196
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000481
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 760 of the PKHD1 protein (p.Arg760His). This variant also falls at the last nucleotide of exon 22, which is part of the consensus splice site for this exon. This variant is present in population databases (rs745770404, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 11898128, 15698423, 20413436). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188876). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24984783). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterresearchBroad Center for Mendelian Genomics, Broad Institute of MIT and Harvard-The heterozygous p.Arg760His variant was identified in the compound heterozygous state by our study in one individual with autosomal recessive polycystic kidney disease. The p.Arg760His variant is believed to be pathogenic based on numberous reports by other laboratories in the literature (Onuchic 2002, Bergmann 2005, Sharp 2005, Gunay-Aygun 2010). -
Likely pathogenic, criteria provided, single submitterliterature onlyCounsylJul 11, 2014- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Jul 28, 2018- -
Likely pathogenic, criteria provided, single submitterresearchMolecular Biology Laboratory, Fundació PuigvertFeb 01, 2020- -
Polycystic kidney disease 4 Pathogenic:3
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CitySep 10, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 26, 2024- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 21, 2024- -
PKHD1-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 06, 2024The PKHD1 c.2279G>A variant is predicted to result in the amino acid substitution p.Arg760His. This substitution occurs at the last nucleotide of exon 22 and is predicted to substantially affect normal splicing by available splicing prediction programs (Alamut Visual Plus v1.6.1). This variant has been reported in individuals with autosomal recessive polycystic kidney disease (ARPKD) (Onuchic et al. 2002. PubMed ID: 11898128; Jordan et al. 2022. PubMed ID: 35005812). Of note, we have previously observed this variant at PreventionGenetics in the homozygous state in an affected child and the heterozygous state in other PKD patients who have another pathogenic PKHD1 variant. The c.2279G>A variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Uncertain
0.022
T
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.34
T;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Benign
0.72
D
LIST_S2
Benign
0.69
T;T
M_CAP
Benign
0.074
D
MetaRNN
Benign
0.29
T;T
MetaSVM
Uncertain
-0.061
T
MutationAssessor
Benign
1.4
L;L
PrimateAI
Benign
0.20
T
PROVEAN
Benign
-1.3
N;N
REVEL
Uncertain
0.49
Sift
Benign
0.53
T;T
Sift4G
Benign
0.075
T;T
Polyphen
0.99
D;D
Vest4
0.16
MVP
0.96
MPC
0.22
ClinPred
0.93
D
GERP RS
5.6
Varity_R
0.056
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.54
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.54
Position offset: 0

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: rs745770404; hg19: chr6-51914955; COSMIC: COSV61868056; API