rs6901799

Positions:

chr6-52082459-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_138694.4(PKHD1):c.214C>T(p.Leu72=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,794 control chromosomes in the GnomAD database, including 9,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L72L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.093 ( 708 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8388 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.398

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 6-52082459-G-A is Benign according to our data. Variant chr6-52082459-G-A is described in ClinVar as [Benign]. Clinvar id is 96385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52082459-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.398 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.214C>T	p.Leu72=	synonymous_variant	4/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.214C>T	p.Leu72=	synonymous_variant	4/67	1	NM_138694.4	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.214C>T	p.Leu72=	synonymous_variant	4/61	5		A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0926

AC:

14090

AN:

152098

Hom.:

701

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0779

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.0879

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.0355

Gnomad SAS

AF:

0.0702

Gnomad FIN

AF:

0.0692

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.108

Gnomad OTH

AF:

0.117

GnomAD3 exomes

AF:

0.0938

AC:

23580

AN:

251360

Hom.:

1238

AF XY:

0.0954

AC XY:

12961

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.0748

Gnomad AMR exome

AF:

0.0721

Gnomad ASJ exome

AF:

0.172

Gnomad EAS exome

AF:

0.0417

Gnomad SAS exome

AF:

0.0818

Gnomad FIN exome

AF:

0.0743

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.104

AC:

151794

AN:

1461576

Hom.:

8388

Cov.:

AF XY:

0.104

AC XY:

75485

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.0797

Gnomad4 AMR exome

AF:

0.0746

Gnomad4 ASJ exome

AF:

0.173

Gnomad4 EAS exome

AF:

0.0441

Gnomad4 SAS exome

AF:

0.0829

Gnomad4 FIN exome

AF:

0.0733

Gnomad4 NFE exome

AF:

0.109

Gnomad4 OTH exome

AF:

0.105

GnomAD4 genome

AF:

0.0928

AC:

14119

AN:

152218

Hom.:

708

Cov.:

AF XY:

0.0913

AC XY:

6795

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0781

Gnomad4 AMR

AF:

0.0879

Gnomad4 ASJ

AF:

0.165

Gnomad4 EAS

AF:

0.0355

Gnomad4 SAS

AF:

0.0701

Gnomad4 FIN

AF:

0.0692

Gnomad4 NFE

AF:

0.108

Gnomad4 OTH

AF:

0.121

Alfa

AF:

0.110

Hom.:

1526

Bravo

AF:

0.0945

Asia WGS

AF:

0.0640

AC:

222

AN:

3478

EpiCase

AF:

0.116

EpiControl

AF:

0.120

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKHD1, p.Leu72Leu variant was identified in 9.3% of 121382 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Polycystic kidney disease 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.85

DANN

Benign

0.46

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