NM_138694.4:c.1587T>C

Variant names:

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.1587T>C(p.Asn529Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0681 in 1,612,956 control chromosomes in the GnomAD database, including 4,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 298 hom., cov: 32)

Exomes 𝑓: 0.070 ( 3902 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.02

Publications

13 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=-0.48).

BP6

Variant 6-52056905-A-G is Benign according to our data. Variant chr6-52056905-A-G is described in ClinVar as Benign. ClinVar VariationId is 96378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.02 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.1587T>C	p.Asn529Asn	synonymous_variant	Exon 17 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.1587T>C	p.Asn529Asn	synonymous_variant	Exon 17 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.1587T>C	p.Asn529Asn	synonymous_variant	Exon 17 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0529

AC:

8040

AN:

152054

Hom.:

298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0396

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.100

Gnomad FIN

AF:

0.0997

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0667

Gnomad OTH

AF:

0.0432

GnomAD2 exomes

AF:

0.0665

AC:

16707

AN:

251138

AF XY:

0.0699

show subpopulations

Gnomad AFR exome

AF:

0.0110

Gnomad AMR exome

AF:

0.0308

Gnomad ASJ exome

AF:

0.0515

Gnomad EAS exome

AF:

0.101

Gnomad FIN exome

AF:

0.0910

Gnomad NFE exome

AF:

0.0685

Gnomad OTH exome

AF:

0.0563

GnomAD4 exome

AF:

0.0697

AC:

101863

AN:

1460784

Hom.:

3902

Cov.:

AF XY:

0.0706

AC XY:

51277

AN XY:

726778

show subpopulations

African (AFR)

AF:

0.00998

AC:

334

AN:

33476

American (AMR)

AF:

0.0333

AC:

1488

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0499

AC:

1304

AN:

26126

East Asian (EAS)

AF:

0.117

AC:

4636

AN:

39680

South Asian (SAS)

AF:

0.0970

AC:

8363

AN:

86226

European-Finnish (FIN)

AF:

0.0911

AC:

4863

AN:

53408

Middle Eastern (MID)

AF:

0.0267

AC:

154

AN:

5766

European-Non Finnish (NFE)

AF:

0.0691

AC:

76798

AN:

1111026

Other (OTH)

AF:

0.0650

AC:

3923

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

4731

9463

14194

18926

23657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2892

5784

8676

11568

14460

<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:

0.0528

AC:

8039

AN:

152172

Hom.:

298

Cov.:

AF XY:

0.0552

AC XY:

4105

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0119

AC:

496

AN:

41524

American (AMR)

AF:

0.0395

AC:

604

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

178

AN:

3472

East Asian (EAS)

AF:

0.109

AC:

562

AN:

5176

South Asian (SAS)

AF:

0.100

AC:

482

AN:

4814

European-Finnish (FIN)

AF:

0.0997

AC:

1056

AN:

10594

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0667

AC:

4537

AN:

67998

Other (OTH)

AF:

0.0432

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

390

781

1171

1562

1952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.0600

Hom.:

193

Bravo

AF:

0.0459

Asia WGS

AF:

0.106

AC:

368

AN:

3474

EpiCase

AF:

0.0613

EpiControl

AF:

0.0638

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

Jan 31, 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

Apr 23, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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.1587T>C, p.Asn529Asn variant was identified in 6.79% of 8219 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

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.48

CADD

Benign

6.2

(source)

DANN

Benign

0.87

PhyloP100

3.0

Mutation Taster

=100/0

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