chr6-52046107-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_138694.4(PKHD1):c.2489A>G(p.Asn830Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0682 in 1,612,894 control chromosomes in the GnomAD database, including 4,189 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 294 hom., cov: 32)

Exomes 𝑓: 0.070 ( 3895 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.983

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 -18 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity PKHD1_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.0015713573).

BP6

Variant 6-52046107-T-C is Benign according to our data. Variant chr6-52046107-T-C is described in ClinVar as [Benign]. Clinvar id is 96391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52046107-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.2489A>G	p.Asn830Ser	missense_variant	Exon 24 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.2489A>G	p.Asn830Ser	missense_variant	Exon 24 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.2489A>G	p.Asn830Ser	missense_variant	Exon 24 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0528

AC:

8037

AN:

152140

Hom.:

294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.0308

Gnomad AMR

AF:

0.0394

Gnomad ASJ

AF:

0.0510

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.100

Gnomad FIN

AF:

0.0992

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0668

Gnomad OTH

AF:

0.0430

GnomAD3 exomes

AF:

0.0666

AC:

16727

AN:

251260

Hom.:

666

AF XY:

0.0699

AC XY:

9490

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.0308

Gnomad ASJ exome

AF:

0.0515

Gnomad EAS exome

AF:

0.101

Gnomad SAS exome

AF:

0.0980

Gnomad FIN exome

AF:

0.0911

Gnomad NFE exome

AF:

0.0685

Gnomad OTH exome

AF:

0.0566

GnomAD4 exome

AF:

0.0698

AC:

101954

AN:

1460636

Hom.:

3895

Cov.:

AF XY:

0.0706

AC XY:

51308

AN XY:

726658

show subpopulations

Gnomad4 AFR exome

AF:

0.00995

Gnomad4 AMR exome

AF:

0.0333

Gnomad4 ASJ exome

AF:

0.0499

Gnomad4 EAS exome

AF:

0.117

Gnomad4 SAS exome

AF:

0.0970

Gnomad4 FIN exome

AF:

0.0913

Gnomad4 NFE exome

AF:

0.0692

Gnomad4 OTH exome

AF:

0.0650

GnomAD4 genome

AF:

0.0528

AC:

8035

AN:

152258

Hom.:

294

Cov.:

AF XY:

0.0550

AC XY:

4098

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0120

Gnomad4 AMR

AF:

0.0394

Gnomad4 ASJ

AF:

0.0510

Gnomad4 EAS

AF:

0.108

Gnomad4 SAS

AF:

0.0998

Gnomad4 FIN

AF:

0.0992

Gnomad4 NFE

AF:

0.0668

Gnomad4 OTH

AF:

0.0430

Alfa

AF:

0.0645

Hom.:

580

Bravo

AF:

0.0459

TwinsUK

AF:

0.0766

AC:

284

ALSPAC

AF:

0.0651

AC:

251

ESP6500AA

AF:

0.0141

AC:

ESP6500EA

AF:

0.0687

AC:

591

ExAC

AF:

0.0678

AC:

8237

Asia WGS

AF:

0.106

AC:

367

AN:

3478

EpiCase

AF:

0.0612

EpiControl

AF:

0.0639

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:6

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Benign - Stand Alone, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 17, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Oct 22, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The c.2489A>G, p.Asn830Ser variant was identified in 6.78% of 8237 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

not provided

Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25701400) -

Polycystic kidney disease 4

Benign:1

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.26

T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0016

T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.9

L;L

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.22

Sift

Benign

0.11

T;T

Sift4G

Benign

0.068

T;T

Polyphen

0.024

B;B

Vest4

0.043

MPC

0.054

ClinPred

0.0049

GERP RS

3.7

Varity_R

0.058

gMVP

0.41

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