rs9381994

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_138694.4(PKHD1):c.12143A>G(p.Gln4048Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 1,613,906 control chromosomes in the GnomAD database, including 248,948 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 21709 hom., cov: 35)

Exomes 𝑓: 0.56 ( 227239 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.422

Publications

38 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=1.0750294E-5).

BP6

Variant 6-51619163-T-C is Benign according to our data. Variant chr6-51619163-T-C is described in ClinVar as Benign. ClinVar VariationId is 96376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.12143A>G	p.Gln4048Arg	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.12143A>G	p.Gln4048Arg	missense_variant	Exon 67 of 67	1	NM_138694.4	ENSP00000360158.3	P08F94-1
ENSG00000228689	ENST00000454361.1 link	n.81-3192T>C		intron_variant	Intron 1 of 1	3
ENSG00000228689	ENST00000589278.6 link	n.811-3197T>C		intron_variant	Intron 2 of 2	5
ENSG00000228689	ENST00000650088.1 link	n.222-3192T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.533

AC:

81013

AN:

152104

Hom.:

21711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.479

Gnomad AMI

AF:

0.397

Gnomad AMR

AF:

0.580

Gnomad ASJ

AF:

0.489

Gnomad EAS

AF:

0.586

Gnomad SAS

AF:

0.643

Gnomad FIN

AF:

0.510

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.550

Gnomad OTH

AF:

0.524

GnomAD2 exomes

AF:

0.566

AC:

142135

AN:

250914

AF XY:

0.566

show subpopulations

Gnomad AFR exome

AF:

0.479

Gnomad AMR exome

AF:

0.650

Gnomad ASJ exome

AF:

0.499

Gnomad EAS exome

AF:

0.585

Gnomad FIN exome

AF:

0.526

Gnomad NFE exome

AF:

0.548

Gnomad OTH exome

AF:

0.554

GnomAD4 exome

AF:

0.556

AC:

813130

AN:

1461684

Hom.:

227239

Cov.:

AF XY:

0.558

AC XY:

406037

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.475

AC:

15907

AN:

33474

American (AMR)

AF:

0.637

AC:

28473

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.492

AC:

12850

AN:

26136

East Asian (EAS)

AF:

0.591

AC:

23451

AN:

39696

South Asian (SAS)

AF:

0.626

AC:

53966

AN:

86256

European-Finnish (FIN)

AF:

0.531

AC:

28346

AN:

53402

Middle Eastern (MID)

AF:

0.573

AC:

3304

AN:

5762

European-Non Finnish (NFE)

AF:

0.552

AC:

613819

AN:

1111858

Other (OTH)

AF:

0.547

AC:

33014

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

22415

44829

67244

89658

112073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17326

34652

51978

69304

86630

<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:

0.532

AC:

81035

AN:

152222

Hom.:

21709

Cov.:

AF XY:

0.532

AC XY:

39565

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.478

AC:

19869

AN:

41532

American (AMR)

AF:

0.580

AC:

8875

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.489

AC:

1696

AN:

3468

East Asian (EAS)

AF:

0.587

AC:

3033

AN:

5170

South Asian (SAS)

AF:

0.643

AC:

3100

AN:

4822

European-Finnish (FIN)

AF:

0.510

AC:

5397

AN:

10592

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.550

AC:

37434

AN:

68010

Other (OTH)

AF:

0.522

AC:

1104

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

2022

4045

6067

8090

10112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

716

1432

2148

2864

3580

<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:

0.545

Hom.:

100866

Bravo

AF:

0.536

TwinsUK

AF:

0.549

AC:

2035

ALSPAC

AF:

0.551

AC:

2125

ESP6500AA

AF:

0.481

AC:

2120

ESP6500EA

AF:

0.549

AC:

4719

ExAC

AF:

0.563

AC:

68311

Asia WGS

AF:

0.597

AC:

2076

AN:

3476

EpiCase

AF:

0.549

EpiControl

AF:

0.554

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 11, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease 4

Benign:3

Jun 19, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Thec.12143A>G, p.Gln4048Arg variant was identified in 56.3% of 68262 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

not provided

Benign:1

Aug 29, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28509106) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.51

MetaRNN

Benign

0.000011

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.5

PhyloP100

0.42

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.75

REVEL

Benign

0.21

Sift

Benign

0.52

Sift4G

Benign

0.25

Polyphen

0.031

Vest4

0.021

MPC

0.064

ClinPred

0.010

GERP RS

4.0

Varity_R

0.046

gMVP

0.16

Mutation Taster

=86/14

polymorphism (auto)

(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