rs9474143

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_138694.4(PKHD1):c.234C>T(p.Asp78Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,612,848 control chromosomes in the GnomAD database, including 56,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7247 hom., cov: 32)

Exomes 𝑓: 0.25 ( 49661 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.45

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 6-52082439-G-A is Benign according to our data. Variant chr6-52082439-G-A is described in ClinVar as [Benign]. Clinvar id is 96388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.45 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.234C>T	p.Asp78Asp	synonymous_variant	Exon 4 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.234C>T	p.Asp78Asp	synonymous_variant	Exon 4 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.234C>T	p.Asp78Asp	synonymous_variant	Exon 4 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45583

AN:

151860

Hom.:

7238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.391

Gnomad AMI

AF:

0.235

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.442

Gnomad SAS

AF:

0.376

Gnomad FIN

AF:

0.323

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.279

GnomAD2 exomes

AF:

0.283

AC:

71060

AN:

251366

AF XY:

0.287

show subpopulations

Gnomad AFR exome

AF:

0.387

Gnomad AMR exome

AF:

0.205

Gnomad ASJ exome

AF:

0.258

Gnomad EAS exome

AF:

0.443

Gnomad FIN exome

AF:

0.317

Gnomad NFE exome

AF:

0.240

Gnomad OTH exome

AF:

0.265

GnomAD4 exome

AF:

0.255

AC:

371930

AN:

1460868

Hom.:

49661

Cov.:

AF XY:

0.257

AC XY:

186713

AN XY:

726782

show subpopulations

African (AFR)

AF:

0.389

AC:

13023

AN:

33450

American (AMR)

AF:

0.212

AC:

9475

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

6670

AN:

26132

East Asian (EAS)

AF:

0.434

AC:

17245

AN:

39698

South Asian (SAS)

AF:

0.359

AC:

30994

AN:

86230

European-Finnish (FIN)

AF:

0.297

AC:

15853

AN:

53414

Middle Eastern (MID)

AF:

0.294

AC:

1697

AN:

5768

European-Non Finnish (NFE)

AF:

0.235

AC:

260590

AN:

1111074

Other (OTH)

AF:

0.271

AC:

16383

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

14032

28063

42095

56126

70158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9136

18272

27408

36544

45680

<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:

0.300

AC:

45614

AN:

151980

Hom.:

7247

Cov.:

AF XY:

0.305

AC XY:

22686

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.391

AC:

16205

AN:

41436

American (AMR)

AF:

0.242

AC:

3693

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

883

AN:

3468

East Asian (EAS)

AF:

0.442

AC:

2273

AN:

5138

South Asian (SAS)

AF:

0.377

AC:

1814

AN:

4816

European-Finnish (FIN)

AF:

0.323

AC:

3408

AN:

10558

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.242

AC:

16449

AN:

67972

Other (OTH)

AF:

0.279

AC:

588

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1579

3157

4736

6314

7893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

472

944

1416

1888

2360

<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:

0.260

Hom.:

11834

Bravo

AF:

0.296

Asia WGS

AF:

0.399

AC:

1383

AN:

3478

EpiCase

AF:

0.245

EpiControl

AF:

0.245

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 11, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2016

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

The c.234C>T, p.Asp78Asp variant was identified in 27.44% of 34517 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

Sep 04, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21790888, 25153916) -

Polycystic kidney disease 4

Benign:1

Jun 19, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.059

(source)

DANN

Benign

0.43

PhyloP100

-1.5

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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