6-51619428-C-T

Position:

chr6-51619428-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_138694.4(PKHD1):c.11878G>A(p.Val3960Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,613,762 control chromosomes in the GnomAD database, including 297 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 17 hom., cov: 33)

Exomes 𝑓: 0.018 ( 280 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.335

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:

ENSG00000228689 (HGNC:):

ENSG00000228689 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=0.004051566).

BP6

Variant 6-51619428-C-T is Benign according to our data. Variant chr6-51619428-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 96375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51619428-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0117 (1790/152346) while in subpopulation NFE AF= 0.018 (1226/68030). AF 95% confidence interval is 0.0172. There are 17 homozygotes in gnomad4. There are 860 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.11878G>A	p.Val3960Ile	missense_variant	67/67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.11878G>A	p.Val3960Ile	missense_variant	67/67	1	NM_138694.4	ENSP00000360158.3	P08F94-1
ENSG00000228689	ENST00000454361.1 linkuse as main transcript	n.81-2927C>T		intron_variant		3
ENSG00000228689	ENST00000589278.6 linkuse as main transcript	n.811-2932C>T		intron_variant		5
ENSG00000228689	ENST00000650088.1 linkuse as main transcript	n.222-2927C>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1788

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00369

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0164

Gnomad FIN

AF:

0.00960

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0144

AC:

3603

AN:

250434

Hom.:

AF XY:

0.0147

AC XY:

1992

AN XY:

135334

show subpopulations

Gnomad AFR exome

AF:

0.00326

Gnomad AMR exome

AF:

0.0209

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0158

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.0171

Gnomad OTH exome

AF:

0.0136

GnomAD4 exome

AF:

0.0181

AC:

26423

AN:

1461416

Hom.:

280

Cov.:

AF XY:

0.0179

AC XY:

13039

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.00302

Gnomad4 AMR exome

AF:

0.0203

Gnomad4 ASJ exome

AF:

0.00984

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0164

Gnomad4 FIN exome

AF:

0.0125

Gnomad4 NFE exome

AF:

0.0199

Gnomad4 OTH exome

AF:

0.0143

GnomAD4 genome

AF:

0.0117

AC:

1790

AN:

152346

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

860

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00368

Gnomad4 AMR

AF:

0.0108

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.0162

Gnomad4 FIN

AF:

0.00960

Gnomad4 NFE

AF:

0.0180

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0163

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0208

AC:

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0166

AC:

143

ExAC

AF:

0.0141

AC:

1718

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive polycystic kidney disease

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2021	This variant is associated with the following publications: (PMID: 26695994) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PKHD1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.41

DANN

Benign

0.79

DEOGEN2

Benign

0.12

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.43

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.20

REVEL

Benign

0.13

Sift

Benign

0.42

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.0090

MPC

0.052

ClinPred

0.0020

GERP RS

0.43

Varity_R

0.025

gMVP

0.071

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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