rs149522482

chr6-52071021-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_138694.4(PKHD1):c.652G>A(p.Glu218Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000541 in 1,601,554 control chromosomes in the GnomAD database, including 2 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 0.0018 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00041 ( 2 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 4.38

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 links:

LOC124901327 (HGNC:):

LOC124901327 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_138694.4

BP4

Computational evidence support a benign effect (MetaRNN=0.029417843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.652G>A	p.Glu218Lys	missense_variant	9/67	ENST00000371117.8
LOC124901327	XR_007059606.1 linkuse as main transcript	n.19C>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.652G>A	p.Glu218Lys	missense_variant	9/67	1	NM_138694.4	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.652G>A	p.Glu218Lys	missense_variant	9/61	5		A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

275

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00522

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.000705

AC:

177

AN:

250922

Hom.:

AF XY:

0.000553

AC XY:

AN XY:

135586

show subpopulations

Gnomad AFR exome

AF:

0.00517

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000300

Gnomad OTH exome

AF:

0.000982

GnomAD4 exome

AF:

0.000409

AC:

593

AN:

1449472

Hom.:

Cov.:

AF XY:

0.000392

AC XY:

283

AN XY:

722068

show subpopulations

Gnomad4 AFR exome

AF:

0.00458

Gnomad4 AMR exome

AF:

0.00145

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000265

Gnomad4 OTH exome

AF:

0.00117

GnomAD4 genome

AF:

0.00180

AC:

274

AN:

152082

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

118

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00518

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000552

Hom.:

Bravo

AF:

0.00214

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000667

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PKHD1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2023	BS1, PP4, PM3 -

Autosomal recessive polycystic kidney disease

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Polycystic kidney disease 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Nov 04, 2021

NM_138694.3(PKHD1):c.652G>A(E218K) is a missense variant classified as a variant of uncertain significance in the context of autosomal recessive polycystic kidney disease, PKHD1-related. E218K has been observed in cases with relevant disease (PMID: 16133180, 27225849, 25701400). Functional assessments of this variant are not available in the literature. E218K has been observed in population frequency databases (gnomAD: AFR 0.51%). In summary, there is insufficient evidence to classify NM_138694.3(PKHD1):c.652G>A(E218K) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Autosomal dominant polycystic liver disease

Benign:1

Likely benign, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

- -

PKHD1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2021

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

0.15

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Pathogenic

0.14

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.029

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

0.88

N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.53

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.076

T;T

Polyphen

0.19

B;B

Vest4

0.95

MVP

0.93

MPC

0.11

ClinPred

0.036

GERP RS

4.3

Varity_R

0.13

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over