6-51619279-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_138694.4(PKHD1):c.12027C>G(p.Tyr4009Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,614,254 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00098 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: PKHD1 NM_138694.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:2
• Conservation: PhyloP100: 0.0380

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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. Fraction of 0.0162 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.12027C>G	p.Tyr4009Ter	stop_gained	67/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.12027C>G	p.Tyr4009Ter	stop_gained	67/67	1	NM_138694.4	P2
	ENST00000589278.6	n.811-3081G>C		intron_variant, non_coding_transcript_variant		5
	ENST00000454361.1	n.81-3076G>C		intron_variant, non_coding_transcript_variant		3
	ENST00000650088.1	n.222-3076G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000939 AC: 143 AN: 152276 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000355 AC: 89 AN: 250814 Hom.: 0 AF XY: 0.000354 AC XY: 48 AN XY: 135524

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000173 AC: 253 AN: 1461860 Hom.: 0 Cov.: 34 AF XY: 0.000184 AC XY: 134 AN XY: 727228

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000984 AC: 150 AN: 152394 Hom.: 1 Cov.: 33 AF XY: 0.000859 AC XY: 64 AN XY: 74522

Gnomad4 AFR AF: 0.00303

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.00103

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000404 AC: 49

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 18, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 02, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2019	Variant summary: PKHD1 c.12027C>G (p.Tyr4009X) results in a premature termination codon in the last exon of the transcript, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. If a stable protein product is made, this nonsense substitution would truncate the protein at codon 4009, which is 66 amino acids from the end of the protein. Truncations downstream of this position have been reported in the literature in two patients (c.12186delT/p.His4063Ilefs*22, PMID 19940839 and c.12036delA/p.Gly4013Alafs*25, PMID 29956005), where one of these individuals had an attenuated phenotype, indicating that a c-terminally truncated fibrocystin could be partially functional (PMID29956005). To our knowledge, no other truncating variants down stream to the variant of interest have been reported in the literature (HGMD), so the significance of a truncation variant in the C-terminal portion of this protein is not known. The variant allele was found at a frequency of 0.00035 in 251214 control chromosomes, predominantly at a frequency of 0.0026 within the African or African-American subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (0.0026 vs 0.0071), allowing no conclusion about variant significance. In addition, at least one known pathogenic PKHD1 variant (c.1486C>T/p.Arg496X) was identified in the gnomAD database at a frequency that is higher than the variant of interest (i.e. 0.0068 in the European Finnish subpopulation), thus it cannot be concluded that c.12027C>G is benign in nature. The variant, c.12027C>G, has been reported in the literature heterozygous state (i.e. without identifying a variant in trans) in two patients, one of them was suspected to be affected with Polycystic Kidney and Hepatic Disease (Bergmann 2004), while the other had isolated polycystic liver disease (Besse 2017). Of note, copy number variants were not tested in these studies therefore these data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2023	Identified as a heterozygous variant in a patient diagnosed at birth with autosomal recessive polycystic kidney disease (ARPKD) in published literature, although a second PKHD1 variant was not identified (Bergmann C et al., 2004); Identified as a heterozygous PKHD1 variant in a patient with polycystic liver disease in published literature (Besse W et al., 2017); Nonsense variant predicted to result in protein truncation, as the last 66 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 15108277, 34426522, 15108281, 28375157, 33226606) -

Polycystic kidney disease 4 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Genomics And Bioinformatics Analysis Resource, Columbia University

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PKHD1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2024

The PKHD1 c.12027C>G variant is predicted to result in premature protein termination (p.Tyr4009*). This variant has been previously reported in the heterozygous state and paternally inherited in an individual diagnosed with polycystic kidney disease (Bergmann et al. 2004. PubMed ID: 15108281). No second variant was reported in the individual, and no functional studies were performed to establish pathogenicity. This variant has also been reported in the heterozygous state in an individual from a cohort of patients with isolated polycystic liver disease who did not present with liver or kidney cysts (L-1224, Besse et al. 2017. PubMed ID: 28375157). Recently, this variant was observed in the compound heterozygous state in a cohort of individuals with chronic kidney disease; and, reported as a variant of uncertain significance (Vaisitti et al. 2021. PubMed ID: 33226606). This variant resides in the final exon of PKHD1 gene, and based on the current knowledge it is unclear if the resulting mRNA would undergo nonsense-mediated decay. This variant is present at a relatively high minor allele frequency of up to ~0.28% in the African sub-population in gnomAD, including one homozygous individual. Given the higher-than-expected minor allele frequency and uncertainty of a nonsense variant in the last exon, we classify this variant as uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.62	D
MutationTaster	Benign	1.0	D
Vest4		0.72
GERP RS		1.4

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

Other links and lift over

dbSNP: rs143616240; hg19: chr6-51484077;