chr6-51883179-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM2PM5PP3_Strong

The NM_138694.4(PKHD1):ā€‹c.7264T>Cā€‹(p.Cys2422Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000559 in 1,610,738 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 Likely pathogenic (ā˜…ā˜…). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2422G) has been classified as Likely pathogenic.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

6
10
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.50
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS1
Transcript NM_138694.4 (PKHD1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-51883179-A-C is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKHD1NM_138694.4 linkc.7264T>C p.Cys2422Arg missense_variant Exon 46 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.7264T>C p.Cys2422Arg missense_variant Exon 46 of 67 1 NM_138694.4 ENSP00000360158.3 P08F94-1
PKHD1ENST00000340994.4 linkc.7264T>C p.Cys2422Arg missense_variant Exon 46 of 61 5 ENSP00000341097.4 P08F94-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251278
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135818
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1458534
Hom.:
0
Cov.:
29
AF XY:
0.00000551
AC XY:
4
AN XY:
725862
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
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:
9.02e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:1
Nov 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2422 of the PKHD1 protein (p.Cys2422Arg). This variant is present in population databases (rs201881567, gnomAD 0.02%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 19914852, 27752906; internal data). 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: 1494871). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1
Dec 18, 2023
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19914852, 27752906) -

Polycystic kidney disease 4 Pathogenic:1
Apr 13, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.44
T;.
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.71
T;T
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.7
M;M
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-4.1
D;D
REVEL
Pathogenic
0.80
Sift
Benign
0.12
T;T
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.98
MutPred
0.95
Gain of MoRF binding (P = 0.0179);Gain of MoRF binding (P = 0.0179);
MVP
0.98
MPC
0.48
ClinPred
0.95
D
GERP RS
5.6
Varity_R
0.71
gMVP
0.96

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: rs201881567; hg19: chr6-51747977; API