rs201881567

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM5PP5BP4

The NM_138694.4(PKHD1):c.7264T>G(p.Cys2422Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000349 in 1,610,856 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2422R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00071 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:6

Conservation

PhyloP100: 5.50

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive polycystic kidney disease
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
polycystic kidney disease 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
Caroli disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-51883179-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1494871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 6-51883179-A-C is Pathogenic according to our data. Variant chr6-51883179-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 406887.

BP4

Computational evidence support a benign effect (MetaRNN=0.1420635). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.7264T>G	p.Cys2422Gly	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
PKHD1	ENST00000371117.8 link	c.7264T>G	p.Cys2422Gly	missense_variant	Exon 46 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.7264T>G	p.Cys2422Gly	missense_variant	Exon 46 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00348

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000501

AC:

126

AN:

251278

AF XY:

0.000530

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00268

Gnomad NFE exome

AF:

0.000493

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000311

AC:

454

AN:

1458534

Hom.:

Cov.:

AF XY:

0.000284

AC XY:

206

AN XY:

725862

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33392

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.000460

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00232

AC:

124

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000269

AC:

298

AN:

1109018

Other (OTH)

AF:

0.000199

AC:

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152322

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00348

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0188

Hom.:

2353

Bravo

AF:

0.000487

ExAC

AF:

0.000469

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Polycystic kidney disease 4

Pathogenic:4Uncertain:3

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Apr 27, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 31, 2023

Human Genetics Bochum, Ruhr University Bochum

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria used to clasify this variant: PM3, PM5, PP3_MOD -

Mar 25, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 15, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3Uncertain:1

Oct 12, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 26, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified with a pathogenic variant on the opposite allele in multiple unrelated patients with polycystic kidney disease in published literature (PMID: 33940108, 15698423); Identified with a second variant (phase unknown) in unrelated patients in published literature (PMID: 12874454, 26489029); 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: 14741187, 20413436, 34405919, 26489029, 27752906, 15698423, 32457805, 12874454, 33940108) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKHD1: PM3:Very Strong, PM2 -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive polycystic kidney disease

Pathogenic:1Uncertain:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 2422 of the PKHD1 protein (p.Cys2422Gly). This variant is present in population databases (rs201881567, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with PKHD1-related conditions (PMID: 12874454, 15698423, 20413436, 26489029, 33940108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 406887). 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 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. -

Dec 02, 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.7264T>G (p.Cys2422Gly) results in a non-conservative amino acid change located in the Parallel beta-helix repeat (IPR006626) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 251278 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0005 vs 0.0071), allowing no conclusion about variant significance. c.7264T>G has been reported in the literature in multiple compound heterozygous individuals affected with Polycystic Kidney And Hepatic Disease and was found to segregate with disease in affected families (e.g. Furu_2003, Bergmann_2005, Braun_2016, Burgmaier_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15698423, 26489029, 33940108, 12874454). ClinVar contains an entry for this variant (Variation ID: 406887). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

PKHD1-related disorder

Pathogenic:1

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKHD1 c.7264T>G variant is predicted to result in the amino acid substitution p.Cys2422Gly. In the compound heterozygous state with different pathogenic PKHD1 variants, this variant has been reported in unrelated individuals with autosomal recessive polycystic kidney disease (ARPKD) (Furu et al. 2003. PubMed ID: 12874454; Bergmann et al. 2005. PubMed ID: 15698423; Supplementary Table 2 at Braun et al. 2016. PubMed ID: 26489029). Of note, a different change affecting the same codon (c.7264T>C, p.Cys2422Arg) has also been reported in an ARPKD individual (Gunay-Aygun et al. 2010. PubMed ID: 19914852). In summary, the c.7264T>G (p.Cys2422Gly) variant is interpreted as likely pathogenic. Of note, this variant has been suggested to be incompletely penetrant (Mikó et al. 2021. PubMed ID: 34405919). -

Autosomal dominant polycystic liver disease

Uncertain:1

Sep 01, 2021

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.74

T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.14

T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

5.5

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-4.1

D;D

REVEL

Pathogenic

0.76

Sift

Benign

0.55

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.97

MVP

0.96

MPC

0.40

ClinPred

0.18

GERP RS

5.6

Varity_R

0.53

gMVP

0.93

Mutation Taster

=9/91

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over