6-52058438-C-G

Position:

• chr6-52058438-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_138694.4(PKHD1):​c.1397G>C​(p.Gly466Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,876 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G466E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 2.70

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_138694.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-52058438-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.1397G>C	p.Gly466Ala	missense_variant	16/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.1397G>C	p.Gly466Ala	missense_variant	16/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.1397G>C	p.Gly466Ala	missense_variant	16/61	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251256 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 20, 2023	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 466 of the PKHD1 protein (p.Gly466Ala). This variant is present in population databases (rs750730042, gnomAD 0.006%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 15698423). ClinVar contains an entry for this variant (Variation ID: 551441). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function. This variant disrupts the p.Gly466 amino acid residue in PKHD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20413436, 27225849, 27752906). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 10, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2023	Variant summary: PKHD1 c.1397G>C (p.Gly466Ala) results in a non-conservative amino acid change located in the PA14/GLEYA domain (IPR037524) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251256 control chromosomes (gnomAD). c.1397G>C has been reported in the literature in heterozygous state (i.e. without identifying a variant in trans) in 3 patients, from two families, where one of them was affected with predominant liver phenotype (Bergmann_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other missense changes affecting the same residue (G466E/R) have been reported in affected individuals (HGMD), and one of them (G466E) is classified as pathogenic by multiple reputable laboratories in ClinVar. The following publication has been ascertained in the context of this evaluation (PMID: 15698423). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Polycystic kidney disease 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 03, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease; however, there are emerging reports of heterozygous carriers of PKHD1 variants developing liver cysts and nephrocalcinosis (PMID: 21945273). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant intrafamilial variability has been reported (PMID: 20301501). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Gly466Glu) has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and p.(Gly466Arg) has been observed as likely compound heterozygous in two individuals with polycystic kidney disease (PMIDs: 34536170, 29520754). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as likely pathogenic or a VUS by clinical laboratories in ClinVar, and has been observed as a single heterozygous variant in two individuals with polycystic kidney disease (PMID: 15698423). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.72	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.54
Sift	Benign	0.081	T;T
Sift4G	Uncertain	0.054	T;T
Polyphen		1.0	D;D
Vest4		0.70
MutPred		0.75		Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);
MVP		0.97
MPC		0.39
ClinPred		0.57	D
GERP RS		5.9
Varity_R		0.21
gMVP		0.51

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: rs750730042; hg19: chr6-51923236;