rs144193508

Positions:

chr6-51619425-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_138694.4(PKHD1):c.11881C>T(p.Arg3961Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R3961R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: -0.272

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-51619425-G-A is Pathogenic according to our data. Variant chr6-51619425-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551016.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.11881C>T	p.Arg3961Ter	stop_gained	67/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.11881C>T	p.Arg3961Ter	stop_gained	67/67	1	NM_138694.4	P2	P08F94-1
	ENST00000589278.6 linkuse as main transcript	n.811-2935G>A		intron_variant, non_coding_transcript_variant		5
	ENST00000454361.1 linkuse as main transcript	n.81-2930G>A		intron_variant, non_coding_transcript_variant		3
	ENST00000650088.1 linkuse as main transcript	n.222-2930G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

250484

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135360

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461366

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

726912

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000740

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Pathogenic:2Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Sep 06, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Arg3961) in the PKHD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 114 amino acid(s) of the PKHD1 protein. This variant is present in population databases (rs144193508, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 34536170; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551016). This variant disrupts a region of the PKHD1 protein in which other variant(s) (p.Pro3968Leufs70) have been observed in individuals with PKHD1-related conditions (PMID: 33940108). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Polycystic kidney disease 4

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	A heterozygous nonsense variant, NM_138694.3(PKHD1):c.11881C>T, has been identified in exon 67 of 67 of the PKHD1 gene. The variant is predicted to result in a premature stop codon at position 3961 of the protein (NP_619639.3(PKHD1):p.(Arg3961*)). This variant is predicted to result in loss of protein function through truncation (although no known functional domains are affected). The variant is present in the gnomAD database at a frequency of 0.0024% (6 heterozygotes, 0 homozygotes). This variant has not been previously reported in clinical cases. Based on the information available at the time of curation, this variant has been classified as VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with POTENTIAL CLINICAL RELEVANCE. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2024	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2022

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 114 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published in an individual with PKHD1-related disease as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22034641, 30275481, 27535533) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Benign

0.95

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.077

MutationTaster

Benign

1.0

Vest4

0.68

GERP RS

-0.92

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