rs147487242

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_138694.4(PKHD1):c.6245C>T(p.Thr2082Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,612,630 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0062 ( 15 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 105 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.493

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034807324).

BP6

Variant 6-51912453-G-A is Benign according to our data. Variant chr6-51912453-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197049.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=1}. Variant chr6-51912453-G-A is described in Lovd as [Benign]. Variant chr6-51912453-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00282 (4119/1460584) while in subpopulation AMR AF= 0.00949 (424/44686). AF 95% confidence interval is 0.00874. There are 105 homozygotes in gnomad4_exome. There are 2007 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.6245C>T	p.Thr2082Ile	missense_variant	Exon 38 of 67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 link	c.6245C>T	p.Thr2082Ile	missense_variant	Exon 38 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.6245C>T	p.Thr2082Ile	missense_variant	Exon 38 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00620

AC:

942

AN:

151928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00840

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00484

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0674

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000809

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00746

AC:

1875

AN:

251240

Hom.:

AF XY:

0.00720

AC XY:

978

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00909

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.00250

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.0614

Gnomad NFE exome

AF:

0.000942

Gnomad OTH exome

AF:

0.00571

GnomAD4 exome

AF:

0.00282

AC:

4119

AN:

1460584

Hom.:

105

Cov.:

AF XY:

0.00276

AC XY:

2007

AN XY:

726700

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00949

Gnomad4 ASJ exome

AF:

0.00276

Gnomad4 EAS exome

AF:

0.00564

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.0551

Gnomad4 NFE exome

AF:

0.000229

Gnomad4 OTH exome

AF:

0.00262

GnomAD4 genome

AF:

0.00620

AC:

942

AN:

152046

Hom.:

Cov.:

AF XY:

0.00921

AC XY:

684

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00852

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00466

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0674

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.000880

Hom.:

Bravo

AF:

0.00192

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00558

AC:

677

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Uncertain:1Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified

Benign:3

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKHD1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

2.7

DANN

Benign

0.23

DEOGEN2

Uncertain

0.65

D;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.54

T;T

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.94

L;L

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.17

Sift

Benign

0.52

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0010

B;B

Vest4

0.10

MVP

0.68

MPC

0.064

ClinPred

0.0047

GERP RS

-3.3

Varity_R

0.045

gMVP

0.69

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