6-51659611-G-T

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.10515C>A(p.Ser3505Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00972 in 1,613,614 control chromosomes in the GnomAD database, including 93 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3505N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0070 ( 5 hom., cov: 32)

Exomes 𝑓: 0.010 ( 88 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.641

Publications

20 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:

LOC124900615 (HGNC:):

LOC124900615 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=0.0075244606).

BP6

Variant 6-51659611-G-T is Benign according to our data. Variant chr6-51659611-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167474.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 = 0.00697 (1060/152174) while in subpopulation NFE AF = 0.0113 (770/67986). AF 95% confidence interval is 0.0107. There are 5 homozygotes in GnomAd4. There are 473 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.10515C>A	p.Ser3505Arg	missense_variant	Exon 61 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.10515C>A	p.Ser3505Arg	missense_variant	Exon 61 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1

Frequencies

GnomAD3 genomes

AF:

0.00696

AC:

1059

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00799

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00684

AC:

1710

AN:

250110

AF XY:

0.00658

show subpopulations

Gnomad AFR exome

AF:

0.00216

Gnomad AMR exome

AF:

0.00595

Gnomad ASJ exome

AF:

0.00428

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00435

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.00854

GnomAD4 exome

AF:

0.0100

AC:

14630

AN:

1461440

Hom.:

Cov.:

AF XY:

0.00978

AC XY:

7112

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

33456

American (AMR)

AF:

0.00619

AC:

276

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00471

AC:

123

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000394

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00489

AC:

261

AN:

53390

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0121

AC:

13401

AN:

1111784

Other (OTH)

AF:

0.00792

AC:

478

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

770

1540

2309

3079

3849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.00697

AC:

1060

AN:

152174

Hom.:

Cov.:

AF XY:

0.00636

AC XY:

473

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41538

American (AMR)

AF:

0.00805

AC:

123

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0113

AC:

770

AN:

67986

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00978

Hom.:

Bravo

AF:

0.00705

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0113

AC:

ExAC

AF:

0.00674

AC:

818

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0111

EpiControl

AF:

0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jan 17, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2019

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PKHD1 c.10515C>A (p.Ser3505Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.007 in 281496 control chromosomes, predominantly at a frequency of 0.011 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism. Though the variant, c.10515C>A, has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease, it has also been found in controls, and therefore multiple studies reported it as a polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Feb 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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 -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive polycystic kidney disease

Benign:3

Jun 30, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKHD1, p.Ser3505Arg variant was identified as a polymorphism in several studies (frequency information not specified) from Spanish, American and British individuals or families with ARPKD/congenital hepatic fibrosis/Caroliâ€šÃ„Ã´s disease, and was present in 6 of 390 control chromosomes (frequency: 0.015) from healthy individuals (Rosetti 2003, Sharp 2005, Losekoot 2005). The variant was also identified in dbSNP (ID: rs139014478) â€šÃ„ÃºWith benign alleleâ€šÃ„Ã¹, Clinvitae database (classification benign), the ClinVar database (classification benign by Emory Genetics Laboratory and Invitae), RWTH AAachen University ARPKD database (classified as a polymorphism); in the 1000 Genomes Project in 22 of 5000 chromosomes (frequency: 0.0044), HAPMAP populations EUR in 11 of 1006 chromosomes (frequency: 0.0109) and AMR in 11 of 694 chromosomes (frequency: 0.0159), NHLBI GO Exome Sequencing Project in 97 of 8600 European American alleles (frequency: 0.0112) and in 10 of 4406 African American alleles (frequency: 0.0022), and in the Exome Aggregation Consortium database (March 14m 2016) in 695 of 66390 chromosomes/ 5 homozygous (frequency: 0.0104) from a population of European (Non-Finnish) individuals, in 68 of 11398 chromosomes/ 1 homozygous (frequency: 0.0104) from a population of Latino individuals and none in the East Asian, Other, African, South Asian, or European (Finnish) populations. The p.Ser3505 residue is mostly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.071

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0075

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

PhyloP100

0.64

PrimateAI

Benign

0.34

PROVEAN

Benign

0.71

REVEL

Benign

0.15

Sift

Benign

0.71

Sift4G

Uncertain

0.0050

Polyphen

0.0060

Vest4

0.30

MutPred

0.34

Gain of catalytic residue at S3505 (P = 0.0082);

MVP

0.75

MPC

0.072

ClinPred

0.011

GERP RS

1.3

Varity_R

0.062

gMVP

0.70

Mutation Taster

=83/17

polymorphism

(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