rs150838488

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000371117.8(PKHD1):c.5768A>T(p.Gln1923Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,613,366 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. Q1923R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

PKHD1
ENST00000371117.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 1.43

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028435498).

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.5768A>T	p.Gln1923Leu	missense_variant	36/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.5768A>T	p.Gln1923Leu	missense_variant	36/67	1	NM_138694.4	ENSP00000360158	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.5768A>T	p.Gln1923Leu	missense_variant	36/61	5		ENSP00000341097	A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00153

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000722

AC:

181

AN:

250646

Hom.:

AF XY:

0.000753

AC XY:

102

AN XY:

135484

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.000982

GnomAD4 exome

AF:

0.00146

AC:

2138

AN:

1461210

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

996

AN XY:

726912

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00181

Gnomad4 OTH exome

AF:

0.00156

GnomAD4 genome

AF:

0.00141

AC:

214

AN:

152156

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00153

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000772

Hom.:

Bravo

AF:

0.00178

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000774

AC:

EpiCase

AF:

0.00142

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15698423, 26489027, 34426522, 34405919, 31308072) -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jun 29, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal recessive polycystic kidney disease

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PKHD1 c.5768A>T (p.Gln1923Leu) variant is a missense variant that has been reported in a compound heterozygous state in one patient with polycystic kidney disease (Bergmann et al. 2005). The p.Gln1923Leu variant was absent from 200 controls but is reported at a frequency of 0.00174 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Gln1923Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 16, 2022

Variant summary: PKHD1 c.5768A>T (p.Gln1923Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 257770 control chromosomes (gnomAD, publications), predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.00072 vs 0.0071), allowing no conclusion about variant significance. c.5768A>T has been reported in the literature in individuals affected with Kidney Disease (Bergmann_2005, Nicolaou_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

PKHD1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2024

The PKHD1 c.5768A>T variant is predicted to result in the amino acid substitution p.Gln1923Leu. This variant was reported, along with a second missense variant in the same gene, in an individual with polycystic kidney disease (Bergmann et al. 2005. PubMed ID: 15698423); however, in another study, this variant was not found to be significantly enriched in an affected patient population (Miko et al. 2021. PubMed ID: 34405919, supplementary data). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.028

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.97

L;L

MutationTaster

Benign

0.90

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.51

Sift

Benign

1.0

T;T

Sift4G

Uncertain

0.033

D;D

Polyphen

0.024

B;B

Vest4

0.59

MVP

0.87

MPC

0.064

ClinPred

0.024

GERP RS

4.5

Varity_R

0.14

gMVP

0.75

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

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