rs9296669

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.3785C>T(p.Ala1262Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,613,692 control chromosomes in the GnomAD database, including 208,329 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 0.41 ( 15058 hom., cov: 31)

Exomes 𝑓: 0.51 ( 193271 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.314

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=1.2064343E-5).

BP6

Variant 6-52026025-G-A is Benign according to our data. Variant chr6-52026025-G-A is described in ClinVar as [Benign]. Clinvar id is 96399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52026025-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4 link	c.3785C>T	p.Ala1262Val	missense_variant	Exon 32 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.3785C>T	p.Ala1262Val	missense_variant	Exon 32 of 67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 link	c.3785C>T	p.Ala1262Val	missense_variant	Exon 32 of 61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.413

AC:

62670

AN:

151922

Hom.:

15058

Cov.:

show subpopulations

Gnomad AFR

AF:

0.158

Gnomad AMI

AF:

0.473

Gnomad AMR

AF:

0.558

Gnomad ASJ

AF:

0.486

Gnomad EAS

AF:

0.353

Gnomad SAS

AF:

0.353

Gnomad FIN

AF:

0.472

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.529

Gnomad OTH

AF:

0.436

GnomAD3 exomes

AF:

0.479

AC:

119919

AN:

250462

Hom.:

30767

AF XY:

0.474

AC XY:

64241

AN XY:

135514

show subpopulations

Gnomad AFR exome

AF:

0.150

Gnomad AMR exome

AF:

0.647

Gnomad ASJ exome

AF:

0.483

Gnomad EAS exome

AF:

0.359

Gnomad SAS exome

AF:

0.359

Gnomad FIN exome

AF:

0.479

Gnomad NFE exome

AF:

0.524

Gnomad OTH exome

AF:

0.507

GnomAD4 exome

AF:

0.507

AC:

740864

AN:

1461652

Hom.:

193271

Cov.:

AF XY:

0.504

AC XY:

366300

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.144

Gnomad4 AMR exome

AF:

0.631

Gnomad4 ASJ exome

AF:

0.483

Gnomad4 EAS exome

AF:

0.327

Gnomad4 SAS exome

AF:

0.363

Gnomad4 FIN exome

AF:

0.500

Gnomad4 NFE exome

AF:

0.533

Gnomad4 OTH exome

AF:

0.482

GnomAD4 genome

AF:

0.412

AC:

62671

AN:

152040

Hom.:

15058

Cov.:

AF XY:

0.409

AC XY:

30424

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.158

Gnomad4 AMR

AF:

0.558

Gnomad4 ASJ

AF:

0.486

Gnomad4 EAS

AF:

0.352

Gnomad4 SAS

AF:

0.353

Gnomad4 FIN

AF:

0.472

Gnomad4 NFE

AF:

0.529

Gnomad4 OTH

AF:

0.433

Alfa

AF:

0.500

Hom.:

48529

Bravo

AF:

0.409

TwinsUK

AF:

0.533

AC:

1976

ALSPAC

AF:

0.517

AC:

1993

ESP6500AA

AF:

0.150

AC:

660

ESP6500EA

AF:

0.517

AC:

4443

ExAC

AF:

0.468

AC:

56845

Asia WGS

AF:

0.325

AC:

1133

AN:

3478

EpiCase

AF:

0.523

EpiControl

AF:

0.517

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala1262Val in exon 32 of PKHD1: This variant is not expected to have clinical significance because it has been identified in 66.59% (7676/11528) of Latino chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs9296669). -

Jan 18, 2017

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

- -

Autosomal recessive polycystic kidney disease

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Polycystic kidney disease 4

Benign:2

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou 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

Thec.3785C>T, p.Ala1262Val variant was identified in 46.98% of 56668 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

Aug 22, 2019

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

0.072

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.098

DANN

Benign

0.90

DEOGEN2

Benign

0.092

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.54

T;T

MetaRNN

Benign

0.000012

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.26

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.13

N;N

REVEL

Benign

0.15

Sift

Benign

0.71

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.0

B;B

Vest4

0.022

MPC

0.060

ClinPred

0.0053

GERP RS

-1.4

Varity_R

0.020

gMVP

0.20

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