rs34548196

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_138694.4(PKHD1):c.11878G>A(p.Val3960Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,613,762 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 17 hom., cov: 33)

Exomes 𝑓: 0.018 ( 280 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.335

Publications

16 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:

ENSG00000228689 (HGNC:):

ENSG00000228689 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004051566).

BP6

Variant 6-51619428-C-T is Benign according to our data. Variant chr6-51619428-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0117 (1790/152346) while in subpopulation NFE AF = 0.018 (1226/68030). AF 95% confidence interval is 0.0172. There are 17 homozygotes in GnomAd4. There are 860 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.11878G>A	p.Val3960Ile	missense_variant	Exon 67 of 67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PKHD1	ENST00000371117.8 link	c.11878G>A	p.Val3960Ile	missense_variant	Exon 67 of 67	1	NM_138694.4	ENSP00000360158.3	P08F94-1
ENSG00000228689	ENST00000454361.1 link	n.81-2927C>T		intron_variant	Intron 1 of 1	3
ENSG00000228689	ENST00000589278.6 link	n.811-2932C>T		intron_variant	Intron 2 of 2	5
ENSG00000228689	ENST00000650088.1 link	n.222-2927C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1788

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00369

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0164

Gnomad FIN

AF:

0.00960

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0144

AC:

3603

AN:

250434

AF XY:

0.0147

show subpopulations

Gnomad AFR exome

AF:

0.00326

Gnomad AMR exome

AF:

0.0209

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.0171

Gnomad OTH exome

AF:

0.0136

GnomAD4 exome

AF:

0.0181

AC:

26423

AN:

1461416

Hom.:

280

Cov.:

AF XY:

0.0179

AC XY:

13039

AN XY:

726944

show subpopulations

African (AFR)

AF:

0.00302

AC:

101

AN:

33474

American (AMR)

AF:

0.0203

AC:

906

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00984

AC:

257

AN:

26106

East Asian (EAS)

AF:

0.000101

AC:

AN:

39686

South Asian (SAS)

AF:

0.0164

AC:

1413

AN:

86226

European-Finnish (FIN)

AF:

0.0125

AC:

669

AN:

53400

Middle Eastern (MID)

AF:

0.00763

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0199

AC:

22164

AN:

1111666

Other (OTH)

AF:

0.0143

AC:

865

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1436

2872

4307

5743

7179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

854

1708

2562

3416

4270

<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:

0.0117

AC:

1790

AN:

152346

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

860

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00368

AC:

153

AN:

41576

American (AMR)

AF:

0.0108

AC:

165

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5186

South Asian (SAS)

AF:

0.0162

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00960

AC:

102

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0180

AC:

1226

AN:

68030

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

188

282

376

470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0161

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0208

AC:

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0166

AC:

143

ExAC

AF:

0.0141

AC:

1718

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive polycystic kidney disease

Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

May 11, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKHD1: BP4, BS1, BS2 -

Feb 12, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26695994) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Polycystic kidney disease 4

Benign:1

Sep 15, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.41

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.12

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.6

PhyloP100

0.34

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.20

REVEL

Benign

0.13

Sift

Benign

0.42

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.0090

MPC

0.052

ClinPred

0.0020

GERP RS

0.43

Varity_R

0.025

gMVP

0.071

Mutation Taster

=99/1

polymorphism

(source)

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

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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