rs1554194574

Positions:

• chr6-52017598-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000371117.8(PKHD1):​c.5411del​(p.Arg1804LeufsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PKHD1 ENST00000371117.8 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: -0.825

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 12 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 6-52017598-AC-A is Pathogenic according to our data. Variant chr6-52017598-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 458602.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.5411del	p.Arg1804LeufsTer18	frameshift_variant	34/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.5411del	p.Arg1804LeufsTer18	frameshift_variant	34/67	1	NM_138694.4	ENSP00000360158	P2
PKHD1	ENST00000340994.4	c.5411del	p.Arg1804LeufsTer18	frameshift_variant	34/61	5		ENSP00000341097	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 458602). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 24162162). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1804Leufs*18) 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). -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 03, 2015	- -

PKHD1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2024

The PKHD1 c.5411delG variant is predicted to result in a frameshift and premature protein termination (p.Arg1804Leufs*18). This variant was reported to be causative for autosomal recessive polycystic kidney disease (Table 1, Krall et al. 2014. PubMed ID: 24162162). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PKHD1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1554194574; hg19: chr6-51882396;