chr6-51748201-C-A

Variant names:

Variant summary

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

The NM_138694.4(PKHD1):c.9415G>T(p.Asp3139Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00566 in 1,614,030 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3139A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 20 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: 0.745

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:

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=0.008653432).

BP6

Variant 6-51748201-C-A is Benign according to our data. Variant chr6-51748201-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167479.

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.9415G>T	p.Asp3139Tyr	missense_variant	Exon 58 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.9415G>T	p.Asp3139Tyr	missense_variant	Exon 58 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.9415G>T	p.Asp3139Tyr	missense_variant	Exon 58 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00395

AC:

601

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00810

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00629

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00415

AC:

1041

AN:

250812

AF XY:

0.00447

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.000895

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00753

Gnomad NFE exome

AF:

0.00621

Gnomad OTH exome

AF:

0.00409

GnomAD4 exome

AF:

0.00583

AC:

8528

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00575

AC XY:

4180

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33470

American (AMR)

AF:

0.000850

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.000651

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00326

AC:

281

AN:

86250

European-Finnish (FIN)

AF:

0.00629

AC:

336

AN:

53410

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00675

AC:

7510

AN:

1111940

Other (OTH)

AF:

0.00495

AC:

299

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

520

1040

1560

2080

2600

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

286

572

858

1144

1430

<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:

0.00395

AC:

601

AN:

152252

Hom.:

Cov.:

AF XY:

0.00392

AC XY:

292

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41554

American (AMR)

AF:

0.000720

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00249

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00810

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00629

AC:

428

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

152

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:

0.00491

Hom.:

Bravo

AF:

0.00301

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00418

AC:

508

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Uncertain:1Benign:6

Aug 18, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2014

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

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. -

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

May 23, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Mar 16, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PKHD1 c.9415G>T (p.Asp3139Tyr) results in a non-conservative amino acid change located in the right handed beta helix domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 277424 control chromosomes, predominantly at a frequency of 0.0075 within the Finnish subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 1.061 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. c.9415G>T has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease (Bergmann_2005, Furu_2003, Gunay-Aygun_2010, Losekoot_2005, Onuchi_2002, rossetti_2003, Ward_2002), however, authors predominantly refer to the variant as a polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKHD1: BP4, BS2 -

Feb 12, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 12874454, 26990548, 11898128, 21228398) -

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.Asp3139Tyr variant was identified in 6 of 888 proband chromosomes (frequency: 0.007) from individuals or families with ARPKD and was present in 13 of 1440 control chromosomes (frequency: 0.009) from healthy individuals (Bergmann 2004, Bergmann 2005, Gunay-Aygun 2010, Losekoot 2005, Rosetti 2003, Sharp 2005). The variant was also identified in dbSNP (ID: rs45503297) as "With other allele", ClinVar (classified as benign by Invitae; and as likely benign by Prevention Genetics, Counsyl, and three other submitters), LOVD 3.0 (4x as likely benign), and in RWTH AAachen University ARPKD database (as polymorphism). The variant was identified in control databases in 1133 of 276504 chromosomes (4 homozygous) at a frequency of 0.004, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 27 of 24022 chromosomes (freq: 0.001), Other in 19 of 6456 chromosomes (freq: 0.003), Latino in 34 of 34376 chromosomes (freq: 0.0009), European in 757 of 126108 chromosomes (freq: 0.006), Ashkenazi Jewish in 9 of 10126 chromosomes (freq: 0.001), Finnish in 193 of 25786 chromosomes (freq: 0.007), and South Asian in 94 of 30780 chromosomes (freq: 0.003), while the variant was not observed in the East Asian population. The p.Asp3139 residue is not 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Polycystic kidney disease 4

Benign:1

May 18, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.0087

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.7

L;L

PhyloP100

0.74

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.17

Sift

Benign

1.0

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0070

B;B

Vest4

0.26

MVP

0.92

MPC

0.078

ClinPred

0.0062

GERP RS

2.9

Varity_R

0.034

gMVP

0.79

Mutation Taster

=95/5

polymorphism

(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