rs794727759

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_138694.4(PKHD1):c.8411T>A(p.Met2804Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,786 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 6.20

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]

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

PP5

Variant 6-51791265-A-T is Pathogenic according to our data. Variant chr6-51791265-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 197958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51791265-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.8411T>A	p.Met2804Lys	missense_variant	Exon 53 of 67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.8411T>A	p.Met2804Lys	missense_variant	Exon 53 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.8411T>A	p.Met2804Lys	missense_variant	Exon 53 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727162

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:

0.0000187

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Pathogenic:4Uncertain:1

May 12, 2020

Laboratory of Molecular Genetics, Children's Memorial Health Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 12, 2017

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Oct 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 2804 of the PKHD1 protein (p.Met2804Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 20413436, 27752906). ClinVar contains an entry for this variant (Variation ID: 197958). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Apr 20, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

this individual was heterozygous for the c.8411T>A variant in the PKHD1 gene. The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). It is listed in ClinVar as a likely pathogenic variant, without any supporting evidence provided. In silico analysis of pathogenicity (through Alamut Visual v2.8.1) is inconclusive regarding this change; SIFT predicts it to be likely pathogenic whereas PolyPhen2 and MutationTaster predicts this variant to be benign. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. Testing of parental specimens (see reports MG-18-02570 & MG-18-02571) indicates that two PKHD1 variants are in trans (on separate alleles). In light of this finding, the c.8411T>A variant has been reclassified as likely pathogenic, according to ACMG guidelines. -

Oct 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKHD1 c.8411T>A (p.Met2804Lys) results in a non-conservative amino acid change located in the G8 domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251266 control chromosomes. c.8411T>A has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (examples: Gunay-Aygun_2010, Tong_2016, Wicher_2020). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 19914852, 33282801, 27752906). ClinVar contains an entry for this variant (Variation ID: 197958). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Jul 21, 2015

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease 4

Pathogenic:1

Oct 22, 2023

Baylor 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

0.78

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.75

D;.

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.8

L;L

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.32

B;B

Vest4

0.93

MutPred

0.76

Gain of ubiquitination at M2804 (P = 0.017);Gain of ubiquitination at M2804 (P = 0.017);

MVP

0.96

MPC

0.26

ClinPred

0.96

GERP RS

5.8

Varity_R

0.89

gMVP

0.89

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over