rs34460237

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.10521C>T(p.His3507His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0481 in 1,613,518 control chromosomes in the GnomAD database, including 2,552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 272 hom., cov: 32)

Exomes 𝑓: 0.048 ( 2280 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.86

Publications

14 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:

LOC124900615 (HGNC:):

LOC124900615 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=-0.89).

BP6

Variant 6-51659605-G-A is Benign according to our data. Variant chr6-51659605-G-A is described in ClinVar as Benign. ClinVar VariationId is 96366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.86 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.10521C>T	p.His3507His	synonymous_variant	Exon 61 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.10521C>T	p.His3507His	synonymous_variant	Exon 61 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1

Frequencies

GnomAD3 genomes

AF:

0.0486

AC:

7389

AN:

152034

Hom.:

269

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00912

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0851

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.133

Gnomad SAS

AF:

0.0702

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0414

Gnomad OTH

AF:

0.0574

GnomAD2 exomes

AF:

0.0661

AC:

16541

AN:

250142

AF XY:

0.0669

show subpopulations

Gnomad AFR exome

AF:

0.00950

Gnomad AMR exome

AF:

0.0831

Gnomad ASJ exome

AF:

0.103

Gnomad EAS exome

AF:

0.130

Gnomad FIN exome

AF:

0.112

Gnomad NFE exome

AF:

0.0439

Gnomad OTH exome

AF:

0.0712

GnomAD4 exome

AF:

0.0480

AC:

70124

AN:

1461364

Hom.:

2280

Cov.:

AF XY:

0.0493

AC XY:

35818

AN XY:

726982

show subpopulations

African (AFR)

AF:

0.00756

AC:

253

AN:

33452

American (AMR)

AF:

0.0854

AC:

3809

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

2824

AN:

26128

East Asian (EAS)

AF:

0.116

AC:

4619

AN:

39684

South Asian (SAS)

AF:

0.0736

AC:

6346

AN:

86244

European-Finnish (FIN)

AF:

0.106

AC:

5673

AN:

53382

Middle Eastern (MID)

AF:

0.0881

AC:

508

AN:

5764

European-Non Finnish (NFE)

AF:

0.0383

AC:

42539

AN:

1111722

Other (OTH)

AF:

0.0589

AC:

3553

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

3815

7630

11444

15259

19074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1696

3392

5088

6784

8480

<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:

0.0487

AC:

7408

AN:

152154

Hom.:

272

Cov.:

AF XY:

0.0546

AC XY:

4064

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00910

AC:

378

AN:

41552

American (AMR)

AF:

0.0857

AC:

1308

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

407

AN:

3470

East Asian (EAS)

AF:

0.133

AC:

681

AN:

5138

South Asian (SAS)

AF:

0.0713

AC:

344

AN:

4824

European-Finnish (FIN)

AF:

0.125

AC:

1326

AN:

10594

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0414

AC:

2818

AN:

68002

Other (OTH)

AF:

0.0582

AC:

123

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

339

678

1018

1357

1696

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0357

Hom.:

124

Bravo

AF:

0.0433

Asia WGS

AF:

0.102

AC:

355

AN:

3478

EpiCase

AF:

0.0433

EpiControl

AF:

0.0431

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 09, 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

- -

Mar 25, 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 PKHD1, p.His3507His variant was identified in 6.2% of 120686 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

-0.89

CADD

Benign

0.056

(source)

DANN

Benign

0.27

PhyloP100

-1.9

Mutation Taster

=94/6

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