rs9474143

Positions:

Variant summary

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

The ENST00000371117.8(PKHD1):c.234C>T(p.Asp78=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,612,848 control chromosomes in the GnomAD database, including 56,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7247 hom., cov: 32)

Exomes 𝑓: 0.25 ( 49661 hom. )

Consequence

PKHD1
ENST00000371117.8 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.45

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 6-52082439-G-A is Benign according to our data. Variant chr6-52082439-G-A is described in ClinVar as [Benign]. Clinvar id is 96388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.45 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.234C>T	p.Asp78=	synonymous_variant	4/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.234C>T	p.Asp78=	synonymous_variant	4/67	1	NM_138694.4	ENSP00000360158	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.234C>T	p.Asp78=	synonymous_variant	4/61	5		ENSP00000341097	A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45583

AN:

151860

Hom.:

7238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.391

Gnomad AMI

AF:

0.235

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.442

Gnomad SAS

AF:

0.376

Gnomad FIN

AF:

0.323

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.279

GnomAD3 exomes

AF:

0.283

AC:

71060

AN:

251366

Hom.:

10854

AF XY:

0.287

AC XY:

38920

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.387

Gnomad AMR exome

AF:

0.205

Gnomad ASJ exome

AF:

0.258

Gnomad EAS exome

AF:

0.443

Gnomad SAS exome

AF:

0.364

Gnomad FIN exome

AF:

0.317

Gnomad NFE exome

AF:

0.240

Gnomad OTH exome

AF:

0.265

GnomAD4 exome

AF:

0.255

AC:

371930

AN:

1460868

Hom.:

49661

Cov.:

AF XY:

0.257

AC XY:

186713

AN XY:

726782

show subpopulations

Gnomad4 AFR exome

AF:

0.389

Gnomad4 AMR exome

AF:

0.212

Gnomad4 ASJ exome

AF:

0.255

Gnomad4 EAS exome

AF:

0.434

Gnomad4 SAS exome

AF:

0.359

Gnomad4 FIN exome

AF:

0.297

Gnomad4 NFE exome

AF:

0.235

Gnomad4 OTH exome

AF:

0.271

GnomAD4 genome

AF:

0.300

AC:

45614

AN:

151980

Hom.:

7247

Cov.:

AF XY:

0.305

AC XY:

22686

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.391

Gnomad4 AMR

AF:

0.242

Gnomad4 ASJ

AF:

0.255

Gnomad4 EAS

AF:

0.442

Gnomad4 SAS

AF:

0.377

Gnomad4 FIN

AF:

0.323

Gnomad4 NFE

AF:

0.242

Gnomad4 OTH

AF:

0.279

Alfa

AF:

0.247

Hom.:

6299

Bravo

AF:

0.296

Asia WGS

AF:

0.399

AC:

1383

AN:

3478

EpiCase

AF:

0.245

EpiControl

AF:

0.245

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

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 c.234C>T, p.Asp78Asp variant was identified in 27.44% of 34517 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

Sep 04, 2019

This variant is associated with the following publications: (PMID: 21790888, 25153916) -

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

-0.86

CADD

Benign

0.059

DANN

Benign

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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