rs137852949

chr6-52058349-G-Achr6-52058349-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_138694.4(PKHD1):c.1486C>T(p.Arg496Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,614,018 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: PKHD1 NM_138694.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 1.10

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-52058349-G-A is Pathogenic according to our data. Variant chr6-52058349-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52058349-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.1486C>T	p.Arg496Ter	stop_gained	16/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.1486C>T	p.Arg496Ter	stop_gained	16/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.1486C>T	p.Arg496Ter	stop_gained	16/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.00811

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000665 AC: 167 AN: 251220 Hom.: 0 AF XY: 0.000707 AC XY: 96 AN XY: 135756

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00674

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000237 AC: 346 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.000232 AC XY: 169 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00577

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000618 AC: 94 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000982 AC XY: 73 AN XY: 74324

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00811

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000568 AC: 69

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:7

Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_138694.3:c.1486C>T in the PKHD1 gene has an allele frequency of 0.007 in European (Finnish) subpopulation in the gnomAD database. The PKHD1 c.1486C>T (p.Arg496*) variant results in a premature termination codon, predicted to cause a truncated or absent PKHD1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant has been reported in patients with autosomal recessive polycystic kidney disease, including six homozygotes, five compound heterozygotes (with V3471G and D2761Y) (PMID: 12506140; 15698423). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PVS1; PM3_Strong, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 03, 2023	This sequence change creates a premature translational stop signal (p.Arg496*) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is present in population databases (rs137852949, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with autosomal recessive polycystic kidney disease (PMID: 12506140, 19914852, 22415584, 27225849). It is commonly reported in individuals of Finnish ancestry (PMID: 12506140). ClinVar contains an entry for this variant (Variation ID: 4114). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 25, 2016	Variant summary: The PKHD1 c.1486C>T (p.Arg496X) variant results in a premature termination codon, predicted to cause a truncated or absent PKHD1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.9319C>T/p.Arg3107X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 69/121402 control chromosomes at a frequency of 0.0005684, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). Variant was primarily detected in Finnish European population in both controls and cases, and it was reported as a founder mutation for Finnish population. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 11, 2019	NM_138694.3(PKHD1):c.1486C>T(R496*) is classified as pathogenic in the context of PKHD1-related autosomal recessive polycystic kidney disease. Sources cited for classification include the following: PMID 12506140 and 15698423. Classification of NM_138694.3(PKHD1):c.1486C>T(R496*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2021	Observed multiple times with a pathogenic variant in published literature and in a patient referred for genetic testing at GeneDx, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Gunay-Aygun et al., 2010); Reported heterozygous in a patient with polycystic liver disease (Besse et al., 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22415584, 25525159, 12506140, 28375157, 15698423, 15200508, 20413436, 33123899) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 22, 2017	- -

Polycystic kidney disease 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 09, 2022	- -

Autosomal dominant polycystic liver disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Apr 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	35
Dann	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.065
FATHMM_MKL	Benign	0.076	N
MutationTaster	Benign	1.0	A;A
Vest4		0.77
GERP RS		2.7

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

Other links and lift over

dbSNP: rs137852949; hg19: chr6-51923147;