6-52058611-A-T

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.1234-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,612,430 control chromosomes in the GnomAD database, including 21,690 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1506 hom., cov: 32)

Exomes 𝑓: 0.16 ( 20184 hom. )

Consequence

PKHD1
NM_138694.4 intron

Scores

Splicing: ADA: 0.6013

Clinical Significance

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

Conservation

PhyloP100: 0.570

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 6-52058611-A-T is Benign according to our data. Variant chr6-52058611-A-T is described in ClinVar as Benign. ClinVar VariationId is 96377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.1234-10T>A		intron_variant	Intron 15 of 66	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.1234-10T>A		intron_variant	Intron 15 of 66	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.1234-10T>A		intron_variant	Intron 15 of 60	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20580

AN:

152070

Hom.:

1496

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0915

Gnomad AMI

AF:

0.263

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.191

Gnomad EAS

AF:

0.0788

Gnomad SAS

AF:

0.191

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.167

Gnomad OTH

AF:

0.155

GnomAD2 exomes

AF:

0.148

AC:

36810

AN:

249096

AF XY:

0.154

show subpopulations

Gnomad AFR exome

AF:

0.0860

Gnomad AMR exome

AF:

0.0932

Gnomad ASJ exome

AF:

0.196

Gnomad EAS exome

AF:

0.0850

Gnomad FIN exome

AF:

0.111

Gnomad NFE exome

AF:

0.172

Gnomad OTH exome

AF:

0.153

GnomAD4 exome

AF:

0.163

AC:

237313

AN:

1460242

Hom.:

20184

Cov.:

AF XY:

0.165

AC XY:

119631

AN XY:

726550

show subpopulations

African (AFR)

AF:

0.0897

AC:

2999

AN:

33436

American (AMR)

AF:

0.0966

AC:

4322

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

5151

AN:

26132

East Asian (EAS)

AF:

0.0872

AC:

3460

AN:

39696

South Asian (SAS)

AF:

0.201

AC:

17335

AN:

86234

European-Finnish (FIN)

AF:

0.111

AC:

5864

AN:

52944

Middle Eastern (MID)

AF:

0.226

AC:

1300

AN:

5764

European-Non Finnish (NFE)

AF:

0.169

AC:

187424

AN:

1110966

Other (OTH)

AF:

0.157

AC:

9458

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

9794

19588

29382

39176

48970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6582

13164

19746

26328

32910

<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:

0.135

AC:

20617

AN:

152188

Hom.:

1506

Cov.:

AF XY:

0.134

AC XY:

9981

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0917

AC:

3807

AN:

41522

American (AMR)

AF:

0.112

AC:

1721

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.191

AC:

664

AN:

3468

East Asian (EAS)

AF:

0.0790

AC:

409

AN:

5176

South Asian (SAS)

AF:

0.191

AC:

924

AN:

4826

European-Finnish (FIN)

AF:

0.103

AC:

1087

AN:

10598

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.167

AC:

11357

AN:

67984

Other (OTH)

AF:

0.159

AC:

336

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

918

1836

2753

3671

4589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

244

488

732

976

1220

<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:

0.0942

Hom.:

174

Bravo

AF:

0.134

Asia WGS

AF:

0.152

AC:

532

AN:

3478

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

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 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. -

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 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.1234-10T>A, p.? variant was identified in 15% of 18201 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

-0.80

CADD

Benign

7.3

(source)

DANN

Benign

0.73

PhyloP100

0.57

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.60

dbscSNV1_RF

Benign

0.66

SpliceAI score (max)

0.020

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