rs1266923

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.5896C>T(p.Leu1966Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0171 in 1,612,946 control chromosomes in the GnomAD database, including 1,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1966L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.050 ( 435 hom., cov: 32)

Exomes 𝑓: 0.014 ( 765 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.81

Publications

5 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 (BayesDel_noAF=-0.56).

BP6

Variant 6-51959882-G-A is Benign according to our data. Variant chr6-51959882-G-A is described in ClinVar as Benign. ClinVar VariationId is 96414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.5896C>T	p.Leu1966Leu	synonymous_variant	Exon 36 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.5896C>T	p.Leu1966Leu	synonymous_variant	Exon 36 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.5896C>T	p.Leu1966Leu	synonymous_variant	Exon 36 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0499

AC:

7585

AN:

151988

Hom.:

430

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0297

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.0367

Gnomad FIN

AF:

0.0657

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.00335

Gnomad OTH

AF:

0.0454

GnomAD2 exomes

AF:

0.0320

AC:

8041

AN:

251106

AF XY:

0.0301

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.0183

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.112

Gnomad FIN exome

AF:

0.0635

Gnomad NFE exome

AF:

0.00428

Gnomad OTH exome

AF:

0.0202

GnomAD4 exome

AF:

0.0137

AC:

19941

AN:

1460840

Hom.:

765

Cov.:

AF XY:

0.0140

AC XY:

10186

AN XY:

726766

show subpopulations

African (AFR)

AF:

0.132

AC:

4405

AN:

33392

American (AMR)

AF:

0.0204

AC:

911

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

287

AN:

26114

East Asian (EAS)

AF:

0.0980

AC:

3890

AN:

39678

South Asian (SAS)

AF:

0.0343

AC:

2954

AN:

86234

European-Finnish (FIN)

AF:

0.0569

AC:

3037

AN:

53410

Middle Eastern (MID)

AF:

0.0315

AC:

181

AN:

5754

European-Non Finnish (NFE)

AF:

0.00253

AC:

2809

AN:

1111250

Other (OTH)

AF:

0.0243

AC:

1467

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

960

1920

2880

3840

4800

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

302

604

906

1208

1510

<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:

0.0501

AC:

7618

AN:

152106

Hom.:

435

Cov.:

AF XY:

0.0526

AC XY:

3910

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.130

AC:

5373

AN:

41468

American (AMR)

AF:

0.0298

AC:

455

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0130

AC:

AN:

3470

East Asian (EAS)

AF:

0.104

AC:

537

AN:

5156

South Asian (SAS)

AF:

0.0365

AC:

176

AN:

4822

European-Finnish (FIN)

AF:

0.0657

AC:

696

AN:

10600

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00335

AC:

228

AN:

67994

Other (OTH)

AF:

0.0445

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

350

700

1051

1401

1751

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0203

Hom.:

226

Bravo

AF:

0.0504

Asia WGS

AF:

0.0780

AC:

272

AN:

3478

EpiCase

AF:

0.00546

EpiControl

AF:

0.00516

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:5

Dec 01, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 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

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 23, 2013

Eurofins Ntd Llc (ga)

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

- -

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The c.5896C>T variant involves the alteration of a conserved nucleotide resulting in a synonymous change. 4/5 in silico tools via Alamut predict no significant effect on splicing. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 3.2%, predominantly observed in the African subpopulation at a frequency of 13.5% including 82 homozygous occurrences. This frequency exceeds the maximal expected allele frequency for a pathogenic variant in PKHD1 (0.71%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. Publications and a clinical lab have classifed the variant as polymorphism/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.Leu1966Leu variant was identified in 2 of 726 proband chromosomes (frequency: 0.003) from individuals or families with ARPKD, and was present in 22 of 920 control chromosomes (frequency: 0.024) from healthy individuals (Bergmann 2005, Furu 2004, Losekoot 2005, Sharp 2005). The variant was also identified in dbSNP (ID: rs1266923) â€šÃ„ÃºWith benign alleleâ€šÃ„Ã¹, in 1000 Genomes Project in 408 of 5006 chromosomes (frequency: 0.0815), in NHLBI GO Exome Sequencing Project in 35 of 8600 (frequency: 0.004) European American and 586 in 4406 (frequency: 0.1285) African American alleles. This variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 3934 of 121262 chromosomes (frequency: 0.03) from a population (frequency) of African (0.14), East Asian (0.11), Finnish (0.06), South Asian (0.04), Other (0.03), Latino (0.02), and European Non-Finnish (0.006) individuals. Furthermore, the variant is listed in the ClinVar database as benign by Emory Genetics Laboratory, in the GeneInsight COGR database as benign by LMM, and in RWTH Aachen University ARPKD database as a polymorphism. The p.Leu1966Leu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant is classified as benign. -

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

-0.56

CADD

Benign

2.8

(source)

DANN

Benign

0.50

PhyloP100

3.8

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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