rs201881567

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 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:8U:5

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]

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-51883179-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id 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 id is 406887.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=7, Pathogenic=1}. Variant chr6-51883179-A-C is described in Lovd as [Likely_pathogenic].

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/exons	MANE	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.7264T>G	p.Cys2422Gly	missense_variant	46/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.7264T>G	p.Cys2422Gly	missense_variant	46/67	1	NM_138694.4	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.7264T>G	p.Cys2422Gly	missense_variant	46/61	5		A2	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

GnomAD3 exomes

AF:

0.000501

AC:

126

AN:

251278

Hom.:

AF XY:

0.000530

AC XY:

AN XY:

135818

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 SAS exome

AF:

0.0000980

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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000460

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00232

Gnomad4 NFE exome

AF:

0.000269

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152322

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00348

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0224

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:8Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Polycystic kidney disease 4

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Jan 31, 2023	ACMG criteria used to clasify this variant: PM3, PM5, PP3_MOD -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 15, 2022	- -
Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

Autosomal recessive polycystic kidney disease

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 27, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 01, 2023	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. A different variant affecting the same amino acid residue has been classified pathogenic in ClinVar, this suggests that this residue may be functionally critical for normal protein function (CV ID 1494871). The following publications have been ascertained in the context of this evaluation (PMID: 15698423, 26489029, 33940108, 12874454). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 21, 2018	The PKHD1 c.7264T>G (p.Cys2422Gly) missense variant has been reported in two studies and found in a total of four individuals with autosomal recessive polycystic kidney disease, including three individuals from two families in a compound heterozygous state and one neonate in a heterozygous state in whom a second variant was not identified (Furu et al. 2003; Bergmann et al. 2005). In all the three compound heterozygous individuals, the p.Cys2422Gly variant was found in trans with an established pathogenic variant, p.Thr36Met. The p.Cys2422Gly variant was absent from a total of 360 controls and is reported at a frequency of 0.00378 in the European (Finnish) population of the Exome Aggregation Consortium. One homozygote is reported in the European (Finnish) population of the Genome Aggregation Database. The evidence for this variant is limited. The p.Cys2422Gly variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	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, 12874454, 33940108, 15698423) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PKHD1: PM3:Strong, PM2, PM5 -

PKHD1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

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. -

Autosomal dominant polycystic liver disease

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

- -

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

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

MutationTaster

Benign

0.98

D;D

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

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