rs149798764

Positions:

chr6-51744505-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PP3_StrongPP5_StrongBS2

The NM_138694.4(PKHD1):c.10036T>C(p.Cys3346Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000238 in 1,613,362 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:17

Conservation

PhyloP100: 5.44

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 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 6-51744505-A-G is Pathogenic according to our data. Variant chr6-51744505-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 198306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=14, Pathogenic=1}. Variant chr6-51744505-A-G is described in Lovd as [Pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.10036T>C	p.Cys3346Arg	missense_variant	60/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.10036T>C	p.Cys3346Arg	missense_variant	60/67	1	NM_138694.4	ENSP00000360158	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.10036T>C	p.Cys3346Arg	missense_variant	60/61	5		ENSP00000341097	A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.000282

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000330

AC:

AN:

251194

Hom.:

AF XY:

0.000376

AC XY:

AN XY:

135736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000493

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000234

AC:

342

AN:

1461020

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

171

AN XY:

726912

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.000804

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000175

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000276

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000348

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Pathogenic:1Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 21, 2018	The PKHD1 c.10036T>C (p.Cys3346Arg) variant is a missense variant that has been reported in a compound heterozygous state in two unrelated individuals with polycystic kidney disease (Rosetti et al. 2003; Tatvira et al. 2015). It has also been reported in a heterozygous state in two individuals with polycystic kidney in whom an alternative molecular diagnosis was identified (Hopp et al. 2011; Eisenberger et al. 2015). The p.Cys3346Arg variant was absent from 50 control individuals but is reported at a frequency of 0.001061 in the Ashkenazi Jewish population of the Genome Aggregation Database. Notably, the variant is reported in a homozygous state in one individual in this population. However, disease severity is variable, and rare cases of adult onset have been reported. Functional studies of this variant have not been conducted. Based on the available evidence, the p.Cys3346Arg variant is classified as of uncertain significance but suspicious for pathogenicity for polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2022	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 3346 of the PKHD1 protein (p.Cys3346Arg). This variant is present in population databases (rs149798764, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 12846734, 25701400). ClinVar contains an entry for this variant (Variation ID: 198306). 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) performed at Invitae indicates that this missense variant is expected to disrupt 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, flagged submission	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:12846734). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

Polycystic kidney disease 4

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 07, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 02, 2023	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 21, 2022	PP3, PM3 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Colon cancer

Pathogenic:1

Pathogenic, flagged submission

curation

Medical Genetics Department, and Science and Technology Unit, Umm-al-Qura University

Oct 06, 2018

It is well established that the PKHD1 mutations are associated with autosomal recessive polycystic kidney disease (ARPKD). It has been shown that the silencing of the PKHD1 gene promotes cell migration and invasion; and in the category of cell adhesion and motility genes PKHD1 has the highest frequency of mutations. Although, PKHD1 mutations are also detected in certain cancer types, to our knowledge in rare tumors such as, amelanotic ano-rectal melanoma (AMM), are not reported. The anorectal- amelanotic melanoma (AMM) represents about 2% - 8% of all melanomas, almost 30% of anorectal melanomas are amelanotic, and they are distinct because they contain a little or no-pigmentation. In order to determine the PKHD1 gene mutation patterns in this tumor we have analyzed the tumor DNA by Ion Proton Next generation DNA sequencing. The present case is from an 84 years old female Saudi patient diagnosed with AMM. This AMM had metastasized to the left-lung in the patient indicating its malignant nature. Next-generation DNA sequencing identified a pathogenic missense mutation (rs149798764) in this tumor, in g.348121T>C, NG_008753.1: on chromosome 6 it changes coding Cys3346Arg in PKHD1 gene. There are 8 submission presents for this variant with variant ID 198306 in ClinVar data base for this mutation. But for the AMM tumors this is the novel finding. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 20, 2024

Variant summary: PKHD1 c.10036T>C (p.Cys3346Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 251394 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 (0.00033 vs 0.0071), allowing no conclusion about variant significance. c.10036T>C has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (Rossetti_2003, Tabira_2015, Domingo-Gallego_2022). These data indicate that the variant may 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: 15805161, 25701400, 12846734, 14741187, 33532864). ClinVar contains an entry for this variant (Variation ID: 198306). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

PKHD1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 03, 2024

The PKHD1 c.10036T>C variant is predicted to result in the amino acid substitution p.Cys3346Arg. This variant has been reported in the compound heterozygous state in an individual with polycystic kidney disease (Rossetti et al. 2003. PubMed ID: 12846734) and in an unknown state in a cohort of individuals with polycystic kidney disease (Sharp et al. 2005. PubMed ID: 15805161). This variant is reported in 0.11% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.63

T;T

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-10

D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.95

MVP

1.0

MPC

0.48

ClinPred

0.90

GERP RS

5.2

Varity_R

0.86

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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