6-51856040-T-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.7764A>G(p.Leu2588Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,592,754 control chromosomes in the GnomAD database, including 114,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 13518 hom., cov: 33)

Exomes 𝑓: 0.35 ( 100668 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.84

Publications

19 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=-0.58).

BP6

Variant 6-51856040-T-C is Benign according to our data. Variant chr6-51856040-T-C is described in ClinVar as Benign. ClinVar VariationId is 96423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.84 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.83 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.7764A>G	p.Leu2588Leu	synonymous_variant	Exon 49 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.7764A>G	p.Leu2588Leu	synonymous_variant	Exon 49 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4 link	c.7764A>G	p.Leu2588Leu	synonymous_variant	Exon 49 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes

AF:

0.402

AC:

61172

AN:

152014

Hom.:

13509

Cov.:

show subpopulations

Gnomad AFR

AF:

0.431

Gnomad AMI

AF:

0.122

Gnomad AMR

AF:

0.531

Gnomad ASJ

AF:

0.260

Gnomad EAS

AF:

0.851

Gnomad SAS

AF:

0.540

Gnomad FIN

AF:

0.452

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.317

Gnomad OTH

AF:

0.370

GnomAD2 exomes

AF:

0.445

AC:

111895

AN:

251352

AF XY:

0.436

show subpopulations

Gnomad AFR exome

AF:

0.433

Gnomad AMR exome

AF:

0.654

Gnomad ASJ exome

AF:

0.253

Gnomad EAS exome

AF:

0.868

Gnomad FIN exome

AF:

0.451

Gnomad NFE exome

AF:

0.315

Gnomad OTH exome

AF:

0.373

GnomAD4 exome

AF:

0.352

AC:

507784

AN:

1440622

Hom.:

100668

Cov.:

AF XY:

0.356

AC XY:

255636

AN XY:

717842

show subpopulations

African (AFR)

AF:

0.417

AC:

13719

AN:

32924

American (AMR)

AF:

0.634

AC:

28350

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.251

AC:

6519

AN:

26020

East Asian (EAS)

AF:

0.828

AC:

32697

AN:

39512

South Asian (SAS)

AF:

0.513

AC:

43939

AN:

85636

European-Finnish (FIN)

AF:

0.436

AC:

23297

AN:

53416

Middle Eastern (MID)

AF:

0.267

AC:

1533

AN:

5736

European-Non Finnish (NFE)

AF:

0.308

AC:

336157

AN:

1092980

Other (OTH)

AF:

0.361

AC:

21573

AN:

59706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

14005

28010

42015

56020

70025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11164

22328

33492

44656

55820

<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:

0.402

AC:

61212

AN:

152132

Hom.:

13518

Cov.:

AF XY:

0.417

AC XY:

31031

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.431

AC:

17882

AN:

41492

American (AMR)

AF:

0.531

AC:

8124

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.260

AC:

902

AN:

3470

East Asian (EAS)

AF:

0.851

AC:

4403

AN:

5172

South Asian (SAS)

AF:

0.539

AC:

2601

AN:

4826

European-Finnish (FIN)

AF:

0.452

AC:

4783

AN:

10584

Middle Eastern (MID)

AF:

0.269

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.317

AC:

21550

AN:

67986

Other (OTH)

AF:

0.368

AC:

777

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1761

3522

5282

7043

8804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<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:

0.343

Hom.:

14896

Bravo

AF:

0.407

Asia WGS

AF:

0.624

AC:

2168

AN:

3478

EpiCase

AF:

0.307

EpiControl

AF:

0.311

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:3

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

- -

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

- -

Oct 22, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease 4

Benign:2

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

- -

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.7764A>G, p.Leu2588Leu variant was identified in 43.39% of 52674 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

8.4

(source)

DANN

Benign

0.72

PhyloP100

1.8

Mutation Taster

=99/1

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