rs78518523

Positions:

chr6-51659200-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138694.4(PKHD1):c.10926G>A(p.Met3642Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,746 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. M3642T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 1 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 0.0390

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:

PKHD1 (HGNC:):

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058997095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.10926G>A	p.Met3642Ile	missense_variant	61/67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.10926G>A	p.Met3642Ile	missense_variant	61/67	1	NM_138694.4	ENSP00000360158.3		P08F94-1

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000677

AC:

170

AN:

250926

Hom.:

AF XY:

0.000671

AC XY:

AN XY:

135598

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00132

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.00138

AC:

2021

AN:

1461594

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

968

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000426

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00173

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000743

AC:

113

AN:

152152

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00140

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.000884

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000708

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2018	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26489027, 16523049, 20981092, 15805161, 20413436, 19914852, 30476936) -

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	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 17, 2017	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Polycystic kidney disease 4

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 24, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 19, 2021	NM_138694.3(PKHD1):c.10926G>A(M3642I) is a missense variant classified as a variant of uncertain significance in the context of autosomal recessive polycystic kidney disease, PKHD1-related. M3642I has been observed in cases with relevant disease (PMID: 19914852, 16523049, 15805161). Functional assessments of this variant are not available in the literature. M3642I has been observed in population frequency databases (gnomAD: NFE 0.13%). In summary, there is insufficient evidence to classify NM_138694.3(PKHD1):c.10926G>A(M3642I) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

PKHD1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2024

The PKHD1 c.10926G>A variant is predicted to result in the amino acid substitution p.Met3642Ile. This variant was reported in individuals with polycystic kidney disease, but the pathogenicity has not been conclusively established (Sharp et al. 2005. PubMed ID: 15805161; Gunay-Aygun et al. 2010. PubMed ID: 19914852; Nicolaou et al. 2016. PubMed ID: 26489027, Supplementary Table 5). This variant is reported in 0.13% 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

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.15

CADD

Benign

4.0

DANN

Benign

0.93

DEOGEN2

Benign

0.092

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.61

M_CAP

Benign

0.038

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.35

REVEL

Uncertain

0.46

Sift

Benign

0.29

Sift4G

Benign

0.19

Polyphen

0.0

Vest4

0.57

MutPred

0.75

Gain of sheet (P = 0.0221);

MVP

0.73

MPC

0.065

ClinPred

0.0083

GERP RS

1.9

Varity_R

0.091

gMVP

0.23

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