rs786204438

Positions:

• chr6-52026043-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_138694.4(PKHD1):​c.3766del​(p.Gln1256ArgfsTer47) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000188 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: PKHD1 NM_138694.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1 B:1
• Conservation: PhyloP100: -0.439

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 11 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 6-52026043-TG-T is Pathogenic according to our data. Variant chr6-52026043-TG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188746.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_benign=1, Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=3}. Variant chr6-52026043-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.3766del	p.Gln1256ArgfsTer47	frameshift_variant	32/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.3766del	p.Gln1256ArgfsTer47	frameshift_variant	32/67	1	NM_138694.4	ENSP00000360158	P2
PKHD1	ENST00000340994.4	c.3766del	p.Gln1256ArgfsTer47	frameshift_variant	32/61	5		ENSP00000341097	A2

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000515 AC: 129 AN: 250668 Hom.: 0 AF XY: 0.000465 AC XY: 63 AN XY: 135626

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00707

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000187 AC: 273 AN: 1461820 Hom.: 0 Cov.: 37 AF XY: 0.000188 AC XY: 137 AN XY: 727206

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00631

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.000430

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000955 Hom.: 0

Bravo AF: 0.000344

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Sep 29, 2020	This frameshifting variant in exon 32 of 67 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in a patient with perinatal onset polycystic kidney disease in whom a second variant was not detected (PMID: 19914852). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.04% (133/282058) and thus is presumed to be rare. Based on the available evidence, the c.3766del (p.Gln1256ArgfsTer47) variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 03, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 27, 2016	The PKHD1 c.3766delC (p.Gln1256ArgfsTer47) variant causes a frameshift and is predicted to result in premature termination of the protein. The p.Gln1256ArgfsTer47 variant has been reported in one individual with autosomal recessive polycystic kidney disease in whom the second variant could not be identified (Gunay-Aygun et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.00191 in the Latino population of the Exome Aggregation Consortium. Due to the potential impact of frameshift variants and the limited evidence available, the p.Gln1256ArgfsTer47 variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Polycystic kidney disease 4 Pathogenic:1 Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 24, 2024

Identified in patients with PKHD1-related phenotypes in published literature (PMID: 28375157, 31738409); Frameshift 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: 31980526, 19914852, 28375157, 31738409, 36978159) -

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs746972457; hg19: chr6-51890841;