rs45500692

Variant names:

• chr6-52055687-G-A
• rs45500692
• NM_138694.4:c.1736C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138694.4(PKHD1):​c.1736C>T​(p.Thr579Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,613,766 control chromosomes in the GnomAD database, including 825 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T579T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (66 hom., cov: 32)
  • Exomes 𝑓: 0.030 (759 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.73
• Publications: 20 publications found

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]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0089610815).
• BP6: Variant 6-52055687-G-A is Benign according to our data. Variant chr6-52055687-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0239 (3643/152252) while in subpopulation NFE AF = 0.0355 (2411/68002). AF 95% confidence interval is 0.0343. There are 66 homozygotes in GnomAd4. There are 1726 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.1736C>T	p.Thr579Met	missense_variant	Exon 19 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.1736C>T	p.Thr579Met	missense_variant	Exon 19 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.1736C>T	p.Thr579Met	missense_variant	Exon 19 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3647 AN: 152134 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.00642

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0246

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0355

Gnomad OTH AF: 0.0240

GnomAD2 exomes AF: 0.0243 AC: 6097 AN: 250966 AF XY: 0.0244

Gnomad AFR exome AF: 0.00604

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0335

Gnomad NFE exome AF: 0.0361

Gnomad OTH exome AF: 0.0217

GnomAD4 exome AF: 0.0300 AC: 43916 AN: 1461514 Hom.: 759 Cov.: 31 AF XY: 0.0295 AC XY: 21464 AN XY: 727068

African (AFR) AF: 0.00484 AC: 162 AN: 33472

American (AMR) AF: 0.0172 AC: 769 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 776 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39692

South Asian (SAS) AF: 0.00579 AC: 499 AN: 86246

European-Finnish (FIN) AF: 0.0291 AC: 1553 AN: 53406

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5758

European-Non Finnish (NFE) AF: 0.0347 AC: 38537 AN: 1111730

Other (OTH) AF: 0.0248 AC: 1495 AN: 60372

GnomAD4 genome AF: 0.0239 AC: 3643 AN: 152252 Hom.: 66 Cov.: 32 AF XY: 0.0232 AC XY: 1726 AN XY: 74452

African (AFR) AF: 0.00640 AC: 266 AN: 41550

American (AMR) AF: 0.0246 AC: 376 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 91 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4824

European-Finnish (FIN) AF: 0.0342 AC: 363 AN: 10608

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0355 AC: 2411 AN: 68002

Other (OTH) AF: 0.0237 AC: 50 AN: 2108

Alfa AF: 0.0316 Hom.: 289

Bravo AF: 0.0224

TwinsUK AF: 0.0337 AC: 125

ALSPAC AF: 0.0402 AC: 155

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0363 AC: 312

ExAC AF: 0.0245 AC: 2980

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0407

EpiControl AF: 0.0394

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Benign:6

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Benign, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 26, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 12, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25701400) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Thr579Met variant was identified in 8 of 1110 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD and was present in 3 of 200 control chromosomes (frequency: 0.015) from healthy individuals (Sharp 2005, Losekoot 2005, Bergmann 2005, Edrees 2016, Obeidova 2015). The variant was also identified in dbSNP (ID: rs45500692) as “With Benign allele”, ClinVar (classified as benign by Invitae and Prevention Genetics), RWTH AAachen University ARPKD database (classified as polynorphism), databases. The variant was not identified in Genesight-COGR, LOVD 3.0, databases. The variant was identified in control databases in 6712 of 276722 chromosomes at a frequency of 0.024255 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Thr579 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein, in addition the variant amino acid Methionine (Met) is present in northern white cheeked gibbon, increasing the likelihood that this variant does not have clinical significance. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Polycystic kidney disease 4 Benign:1

Jun 19, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0090	T;T
MetaSVM	Uncertain	0.016	D
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		2.7
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.25
Sift	Benign	0.13	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.15
MPC		0.37
ClinPred		0.019	T
GERP RS		3.7
Varity_R		0.043
gMVP		0.64
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45500692; hg19: chr6-51920485; COSMIC: COSV61866124;