6-52024589-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_138694.4(PKHD1):​c.5221G>A​(p.Val1741Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

1
10
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:5

Conservation

PhyloP100: 1.40
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_pathogenic. Variant got 7 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_138694.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.894
PP5
Variant 6-52024589-C-T is Pathogenic according to our data. Variant chr6-52024589-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4111.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=3, Uncertain_significance=5}. Variant chr6-52024589-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PKHD1NM_138694.4 linkuse as main transcriptc.5221G>A p.Val1741Met missense_variant 32/67 ENST00000371117.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PKHD1ENST00000371117.8 linkuse as main transcriptc.5221G>A p.Val1741Met missense_variant 32/671 NM_138694.4 P2P08F94-1
PKHD1ENST00000340994.4 linkuse as main transcriptc.5221G>A p.Val1741Met missense_variant 32/615 A2P08F94-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152196
Hom.:
0
Cov.:
32
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
250908
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135754
show subpopulations
Gnomad AFR exome
AF:
0.0000618
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000390
AC:
57
AN:
1461798
Hom.:
0
Cov.:
34
AF XY:
0.0000358
AC XY:
26
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000486
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152196
Hom.:
0
Cov.:
32
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000295
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:4Uncertain:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2002- -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylAug 02, 2017- -
Likely pathogenic, criteria provided, single submitterresearchCavalleri Lab, Royal College of Surgeons in IrelandFeb 05, 2020PS1, PM3, PP2, PP3, PP4 -
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 20, 2023This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1741 of the PKHD1 protein (p.Val1741Met). This variant is present in population databases (rs137852946, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of polycystic kidney disease (PMID: 11919560, 12846734, 19914852, 30773290; Invitae). 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: 4111). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic. -
Polycystic kidney disease 4 Pathogenic:2Uncertain:1
Pathogenic, no assertion criteria providedliterature onlyYale Center for Mendelian Genomics, Yale UniversityFeb 14, 2019- -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 27, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJul 17, 2023Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease; however, there are emerging reports of heterozygous carriers of PKHD1 variants developing liver cysts and nephrocalcinosis (PMID: 21945273). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant intrafamilial variability has been reported (PMID: 20301501). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (9 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as pathogenic, likely pathogenic and as a VUS by clinical laboratories in ClinVar. This variant has also been observed in the literature as a single heterozygous variant, with other PKHD1 variants (not confirmed to be in trans), and also as homozygous in individuals with ARPKD or related phenotypes (PMIDs: 21945273, 11919560, 12846734, 19914852, 20413436, 30773290, 35372954). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 11, 2014- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 28, 2023Identified as a single heterozygous variant in an individual with polycystic kidney disease and in an individual with liver cysts (Ward et al., 2002; Gunay-Aygun et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21945273, 11919560, 30773290, 35372954, 12846734, 34405919, 33454723) -
See cases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University Hospital MuensterDec 21, 2021ACMG categories: PM1,PM2,PP3 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Uncertain
0.090
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.47
T;.
Eigen
Benign
0.17
Eigen_PC
Benign
0.031
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.78
T;T
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Uncertain
0.64
D
MutationAssessor
Uncertain
2.7
M;M
MutationTaster
Benign
1.2e-9
A;A
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-2.3
N;N
REVEL
Uncertain
0.50
Sift
Uncertain
0.0050
D;D
Sift4G
Uncertain
0.0060
D;D
Polyphen
0.99
D;D
Vest4
0.70
MVP
0.95
MPC
0.36
ClinPred
0.77
D
GERP RS
4.7
Varity_R
0.13
gMVP
0.43

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs137852946; hg19: chr6-51889387; API