rs2499481

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.3686G>C(p.Trp1229Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,614,094 control chromosomes in the GnomAD database, including 59 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 0.0099 ( 33 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 26 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.896

Publications

3 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008166671).

BP6

Variant 6-52026124-C-G is Benign according to our data. Variant chr6-52026124-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0099 (1507/152252) while in subpopulation AFR AF = 0.0334 (1388/41538). AF 95% confidence interval is 0.032. There are 33 homozygotes in GnomAd4. There are 662 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.3686G>C	p.Trp1229Ser	missense_variant	Exon 32 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.3686G>C	p.Trp1229Ser	missense_variant	Exon 32 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.3686G>C	p.Trp1229Ser	missense_variant	Exon 32 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00991

AC:

1508

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0335

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00276

AC:

688

AN:

249532

AF XY:

0.00197

show subpopulations

Gnomad AFR exome

AF:

0.0335

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000331

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00112

AC:

1633

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

728

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0319

AC:

1069

AN:

33480

American (AMR)

AF:

0.00333

AC:

149

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00641

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000210

AC:

234

AN:

1111990

Other (OTH)

AF:

0.00230

AC:

139

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

194

291

388

485

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00990

AC:

1507

AN:

152252

Hom.:

Cov.:

AF XY:

0.00889

AC XY:

662

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0334

AC:

1388

AN:

41538

American (AMR)

AF:

0.00556

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

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:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68010

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

139

209

278

348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00308

Hom.:

Bravo

AF:

0.0114

ESP6500AA

AF:

0.0352

AC:

155

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00350

AC:

425

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 18, 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.3686G>C (p.Trp1229Ser) results in a non-conservative amino acid change located in the IPT domain (IPR002909) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0034 in 280922 control chromosomes, predominantly at a frequency of 0.033 within the African or African-American subpopulation in the gnomAD database, including 18 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 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 found primarily in populations of African or African-American origin. The variant, c.3686G>C, has been reported in the literature in individuals affected with juvenile myoclonic epilepsy or Autosomal recessive polycystic kidney disease (Suzuki_2006, Melchionda_2016). These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney and Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as benign (2x) and likely pathogenic (1x). 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

- -

Feb 23, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive polycystic kidney disease

Benign:3

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

May 17, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 27, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16876319, 27225849) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKHD1: BP4, BS1, BS2 -

Polycystic kidney disease 4

Benign:2

Jun 29, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2017

Counsyl

Significance:Likely benign

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.49

CADD

Benign

7.6

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.65

N;N

PhyloP100

0.90

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.098

Sift

Benign

0.96

T;T

Sift4G

Benign

0.73

T;T

Polyphen

0.010

B;B

Vest4

0.29

MVP

0.84

MPC

0.096

ClinPred

0.0035

GERP RS

3.1

Varity_R

0.14

gMVP

0.41

Mutation Taster

=97/3

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