chr6-52024685-G-A

Variant names:

• chr6-52024685-G-A
• rs45517932
• NM_138694.4:c.5125C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138694.4(PKHD1):​c.5125C>T​(p.Leu1709Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00598 in 1,614,206 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (42 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 6.54
• Publications: 17 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0142250955).
• BP6: Variant 6-52024685-G-A is Benign according to our data. Variant chr6-52024685-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262404.
• BS2: High Homozygotes in GnomAdExome4 at 42 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.5125C>T	p.Leu1709Phe	missense	Exon 32 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.5125C>T	p.Leu1709Phe	missense	Exon 32 of 61	NP_733842.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.5125C>T	p.Leu1709Phe	missense	Exon 32 of 67	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.5125C>T	p.Leu1709Phe	missense	Exon 32 of 61	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00636

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00282 AC: 709 AN: 251342 AF XY: 0.00297

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00528

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00623 AC: 9103 AN: 1461870 Hom.: 42 Cov.: 34 AF XY: 0.00603 AC XY: 4387 AN XY: 727238

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00168 AC: 75 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86258

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00770 AC: 8567 AN: 1111990

Other (OTH) AF: 0.00654 AC: 395 AN: 60394

GnomAD4 genome AF: 0.00364 AC: 554 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.00322 AC XY: 240 AN XY: 74490

African (AFR) AF: 0.00140 AC: 58 AN: 41568

American (AMR) AF: 0.00353 AC: 54 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00636 AC: 433 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00484 Hom.: 2

Bravo AF: 0.00362

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00240 AC: 291

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 08, 2017

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

not provided Uncertain:1 Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKHD1: BS2

Mar 06, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1

Jun 26, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24162162, 30809968, 19940839, 20413436, 16133180, 15805161, 15108277, 12874454, 12846734)

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 18, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 15, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKHD1 c.5125C>T (p.Leu1709Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 251342 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.0053 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney And Hepatic Disease (0.0028 vs 0.0071), allowing no conclusion about variant significance. However, this variant was observed in high allele frequency (as high as 1.5%) in healthy controls in multiple publications and classified as polymorphism (Rossetti_2003, Bergmann_2014, Sharp_2005, Losekoot_2005). c.5125C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Furu_2003, Gunay-Aygun_2010, Denamur_2010, Bullich_2018). These reports do not provide unequivocal conclusions about association of the variant with Polycystic Kidney And Hepatic Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: two have classified the variant as of uncertain significance and four have classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

Polycystic kidney disease 4 Benign:1

Aug 27, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.61
Sift	Benign	0.13	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.53
MVP		0.95
MPC		0.39
ClinPred		0.033	T
GERP RS		4.7
Varity_R		0.12
gMVP		0.40
Mutation Taster		=86/14	polymorphism

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: rs45517932; hg19: chr6-51889483; COSMIC: COSV99049427;