chr6-51648091-G-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.11338C>T(p.Pro3780Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0021 in 1,606,254 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P3780P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 7 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 3.73

Publications

8 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=0.02890262).

BP6

Variant 6-51648091-G-A is Benign according to our data. Variant chr6-51648091-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216820.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.11338C>T	p.Pro3780Ser	missense	Exon 63 of 67	NP_619639.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.11338C>T	p.Pro3780Ser	missense	Exon 63 of 67	ENSP00000360158.3

Frequencies

GnomAD3 genomes

AF:

0.00134

AC:

204

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00143

AC:

358

AN:

251046

AF XY:

0.00137

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00255

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00218

AC:

3169

AN:

1453976

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1590

AN XY:

723900

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

33348

American (AMR)

AF:

0.00123

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26082

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39660

South Asian (SAS)

AF:

0.000418

AC:

AN:

86120

European-Finnish (FIN)

AF:

0.000412

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00265

AC:

2927

AN:

1104702

Other (OTH)

AF:

0.00179

AC:

108

AN:

60186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

130

260

391

521

651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00134

AC:

204

AN:

152278

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41574

American (AMR)

AF:

0.00124

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00240

AC:

163

AN:

68018

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.00222

Hom.:

Bravo

AF:

0.00158

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00156

AC:

190

EpiCase

AF:

0.00284

EpiControl

AF:

0.00302

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Autosomal recessive polycystic kidney disease (3)

not specified (1)

PKHD1-related disorder (1)

Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

M_CAP

Benign

0.044

MetaRNN

Benign

0.029

MetaSVM

Uncertain

0.092

MutationAssessor

Uncertain

2.2

PhyloP100

3.7

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.7

REVEL

Benign

0.28

Sift

Benign

0.21

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.45

MVP

0.97

MPC

0.20

ClinPred

0.083

GERP RS

5.2

Varity_R

0.082

gMVP

0.47

Mutation Taster

=35/65

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over