rs4715227

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_138694.4(PKHD1):c.11696A>G(p.Gln3899Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,608,696 control chromosomes in the GnomAD database, including 243,945 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 21359 hom., cov: 31)

Exomes 𝑓: 0.55 ( 222586 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.13

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.6837726E-5).

BP6

Variant 6-51627086-T-C is Benign according to our data. Variant chr6-51627086-T-C is described in ClinVar as [Benign]. Clinvar id is 96372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51627086-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.11696A>G	p.Gln3899Arg	missense_variant	Exon 66 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.11696A>G	p.Gln3899Arg	missense_variant	Exon 66 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1

Frequencies

GnomAD3 genomes

AF:

0.529

AC:

80278

AN:

151796

Hom.:

21362

Cov.:

show subpopulations

Gnomad AFR

AF:

0.480

Gnomad AMI

AF:

0.389

Gnomad AMR

AF:

0.577

Gnomad ASJ

AF:

0.451

Gnomad EAS

AF:

0.557

Gnomad SAS

AF:

0.629

Gnomad FIN

AF:

0.505

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.548

Gnomad OTH

AF:

0.514

GnomAD3 exomes

AF:

0.559

AC:

140351

AN:

251288

Hom.:

39520

AF XY:

0.557

AC XY:

75694

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.482

Gnomad AMR exome

AF:

0.645

Gnomad ASJ exome

AF:

0.466

Gnomad EAS exome

AF:

0.560

Gnomad SAS exome

AF:

0.616

Gnomad FIN exome

AF:

0.521

Gnomad NFE exome

AF:

0.544

Gnomad OTH exome

AF:

0.540

GnomAD4 exome

AF:

0.551

AC:

803362

AN:

1456782

Hom.:

222586

Cov.:

AF XY:

0.553

AC XY:

400989

AN XY:

725000

show subpopulations

Gnomad4 AFR exome

AF:

0.477

Gnomad4 AMR exome

AF:

0.632

Gnomad4 ASJ exome

AF:

0.457

Gnomad4 EAS exome

AF:

0.559

Gnomad4 SAS exome

AF:

0.613

Gnomad4 FIN exome

AF:

0.525

Gnomad4 NFE exome

AF:

0.550

Gnomad4 OTH exome

AF:

0.538

GnomAD4 genome

AF:

0.529

AC:

80300

AN:

151914

Hom.:

21359

Cov.:

AF XY:

0.527

AC XY:

39145

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.480

Gnomad4 AMR

AF:

0.576

Gnomad4 ASJ

AF:

0.451

Gnomad4 EAS

AF:

0.557

Gnomad4 SAS

AF:

0.628

Gnomad4 FIN

AF:

0.505

Gnomad4 NFE

AF:

0.548

Gnomad4 OTH

AF:

0.513

Alfa

AF:

0.543

Hom.:

54455

Bravo

AF:

0.532

TwinsUK

AF:

0.553

AC:

2050

ALSPAC

AF:

0.549

AC:

2114

ESP6500AA

AF:

0.481

AC:

2120

ESP6500EA

AF:

0.545

AC:

4690

ExAC

AF:

0.555

AC:

67367

Asia WGS

AF:

0.577

AC:

2007

AN:

3476

EpiCase

AF:

0.542

EpiControl

AF:

0.546

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:3

Jan 12, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease 4

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 19, 2021

Pars Genome Lab

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.11696A>G, p.Gln3899Arg variant was identified in 55.5% of 67337 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.085

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.45

MetaRNN

Benign

0.000047

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.95

REVEL

Benign

0.27

Sift

Benign

0.034

Sift4G

Benign

0.067

Polyphen

0.29

Vest4

0.13

MPC

0.094

ClinPred

0.015

GERP RS

4.0

Varity_R

0.11

gMVP

0.42

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