rs149781976

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_138694.4(PKHD1):c.1342G>C(p.Gly448Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,614,188 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 7 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:3

Conservation

PhyloP100: 0.403

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029243797).

BP6

Variant 6-52058493-C-G is Benign according to our data. Variant chr6-52058493-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 374479.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.1342G>C	p.Gly448Arg	missense_variant	Exon 16 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.1342G>C	p.Gly448Arg	missense_variant	Exon 16 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.1342G>C	p.Gly448Arg	missense_variant	Exon 16 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

238

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00216

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00159

AC:

399

AN:

251142

AF XY:

0.00141

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000785

Gnomad NFE exome

AF:

0.00258

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00206

AC:

3011

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

1454

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.00150

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000777

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000842

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00242

AC:

2695

AN:

1111990

Other (OTH)

AF:

0.00202

AC:

122

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

182

363

545

726

908

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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:

0.00156

AC:

238

AN:

152320

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41570

American (AMR)

AF:

0.00366

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00216

AC:

147

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00162

Hom.:

Bravo

AF:

0.00184

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00190

AC:

231

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6Benign:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKHD1 p.Gly448Arg variant was identified in 4 of 618 proband chromosomes (frequency: 0.0065) from individuals with polycystic kidney disease (Eisenberger_2015_PMID:25646624; Bergmann_2005_PMID:15698423; Vora_2017_PMID:28518170; Sharp_2005_PMID:15805161). The variant was identified in dbSNP (ID: rs149781976), LOVD 3.0, ClinVar (classified as uncertain significance by EGL genetics, CeGaT Praxis fuer Humangenetik Tuebingen, Fulgent Genetics and Counsyl for autosomal recessive polycystic kidney disease, and as likely benign by Invitae) and the RWTH AAachen University ARPKD database. The variant was identified in control databases in 445 of 282546 chromosomes at a frequency of 0.001575 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 330 of 128880 chromosomes (freq: 0.002561), Other in 14 of 7220 chromosomes (freq: 0.001939), Latino in 54 of 35432 chromosomes (freq: 0.001524), European (Finnish) in 19 of 25122 chromosomes (freq: 0.000756), South Asian in 16 of 30616 chromosomes (freq: 0.000523), African in 11 of 24968 chromosomes (freq: 0.000441) and Ashkenazi Jewish in 1 of 10358 chromosomes (freq: 0.000097), but was not observed in the East Asian population. The p.Gly448 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Feb 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29642553, 25646624, 28492530, 26489027, 15805161, 21228398, 15698423) -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 31, 2016

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive polycystic kidney disease

Uncertain:3Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 08, 2017

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal dominant polycystic liver disease

Uncertain:1

Sep 01, 2021

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Polycystic kidney disease 4

Uncertain:1

Oct 17, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

PKHD1-related disorder

Benign:1

Sep 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

0.10

Eigen_PC

Benign

-0.030

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.78

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.029

T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

0.40

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

1.0

D;D

Vest4

0.75

MVP

0.90

MPC

0.12

ClinPred

0.040

GERP RS

4.1

Varity_R

0.16

gMVP

0.61

Mutation Taster

=21/79

disease causing

(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