rs141790557

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_138694.4(PKHD1):c.158A>G(p.Asn53Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,614,118 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 9 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -0.0380

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062810183).

BP6

Variant 6-52082515-T-C is Benign according to our data. Variant chr6-52082515-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197367.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.158A>G	p.Asn53Ser	missense_variant	4/67	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.158A>G	p.Asn53Ser	missense_variant	4/67	1	NM_138694.4	ENSP00000360158	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.158A>G	p.Asn53Ser	missense_variant	4/61	5		ENSP00000341097	A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00154

AC:

234

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00270

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00108

AC:

271

AN:

251384

Hom.:

AF XY:

0.00112

AC XY:

152

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00194

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00180

AC:

2634

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

1318

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.000827

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.000449

Gnomad4 NFE exome

AF:

0.00221

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00154

AC:

234

AN:

152284

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00271

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00215

Hom.:

Bravo

AF:

0.00138

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00101

AC:

123

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00142

EpiControl

AF:

0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 08, 2017	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PKHD1: BP4, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 24, 2016

- -

PKHD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 13, 2023

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

0.055

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Benign

2.0

DANN

Benign

0.35

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.57

N;N

REVEL

Benign

0.16

Sift

Benign

0.78

T;T

Sift4G

Benign

0.83

T;T

Polyphen

0.0030

B;B

Vest4

0.060

MVP

0.61

MPC

0.050

ClinPred

0.0025

GERP RS

-2.9

Varity_R

0.029

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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