6-51791331-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_138694.4(PKHD1):c.8345G>C(p.Gly2782Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00406 in 1,613,232 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts 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. G2782E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 14 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6B:12

Conservation

PhyloP100: 5.24

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02626586).

BS2

High Homozygotes in GnomAdExome4 at 14 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.8345G>C	p.Gly2782Ala	missense	Exon 53 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.8345G>C	p.Gly2782Ala	missense	Exon 53 of 61	NP_733842.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.8345G>C	p.Gly2782Ala	missense	Exon 53 of 67	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.8345G>C	p.Gly2782Ala	missense	Exon 53 of 61	ENSP00000341097.4

Frequencies

GnomAD3 genomes

AF:

0.00246

AC:

374

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000918

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00426

Gnomad OTH

AF:

0.00384

GnomAD2 exomes

AF:

0.00266

AC:

668

AN:

251184

AF XY:

0.00267

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.000926

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00496

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00422

AC:

6171

AN:

1461030

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

2985

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33468

American (AMR)

AF:

0.00101

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00210

AC:

112

AN:

53420

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00521

AC:

5786

AN:

1111262

Other (OTH)

AF:

0.00311

AC:

188

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

287

575

862

1150

1437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

226

452

678

904

1130

<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:

0.00246

AC:

374

AN:

152202

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

158

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000915

AC:

AN:

41516

American (AMR)

AF:

0.00131

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00426

AC:

290

AN:

68032

Other (OTH)

AF:

0.00380

AC:

AN:

2108

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:

0.00359

Hom.:

Bravo

AF:

0.00271

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00264

AC:

321

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00524

EpiControl

AF:

0.00421

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Autosomal recessive polycystic kidney disease (4)

not specified (4)

Autosomal dominant polycystic liver disease (1)

Caroli disease (1)

Kidney failure (1)

PKHD1-related disorder (1)

Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.026

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.1

PhyloP100

5.2

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.43

Sift

Benign

0.37

Sift4G

Benign

0.11

Polyphen

0.95

Vest4

0.56

MVP

0.96

MPC

0.37

ClinPred

0.070

GERP RS

5.7

Varity_R

0.31

gMVP

0.68

Mutation Taster

=80/20

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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