rs76572975

Variant names:

• chr6-51632705-C-A
• rs76572975
• NM_138694.4:c.11525G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-51632705-C-A
• chr6-51632705-C-G
• chr6-51632705-C-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.11525G>T​(p.Arg3842Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,612,948 control chromosomes in the GnomAD database, including 441 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3842Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (35 hom., cov: 32)
  • Exomes 𝑓: 0.021 (406 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.69
• Publications: 19 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=0.0076598525).
• BP6: Variant 6-51632705-C-A is Benign according to our data. Variant chr6-51632705-C-A is described in ClinVar as Benign. ClinVar VariationId is 96371.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 = 0.0173 (2633/151962) while in subpopulation NFE AF = 0.0231 (1572/67968). AF 95% confidence interval is 0.0222. There are 35 homozygotes in GnomAd4. There are 1347 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.11525G>T	p.Arg3842Leu	missense_variant	Exon 65 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.11525G>T	p.Arg3842Leu	missense_variant	Exon 65 of 67	1	NM_138694.4	ENSP00000360158.3

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2636 AN: 151844 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00423

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.0437

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0189 AC: 4729 AN: 250844 AF XY: 0.0192

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0416

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0207 AC: 30239 AN: 1460986 Hom.: 406 Cov.: 31 AF XY: 0.0207 AC XY: 15058 AN XY: 726798

African (AFR) AF: 0.00472 AC: 158 AN: 33442

American (AMR) AF: 0.0123 AC: 551 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 601 AN: 26108

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39674

South Asian (SAS) AF: 0.00899 AC: 775 AN: 86232

European-Finnish (FIN) AF: 0.0378 AC: 2020 AN: 53390

Middle Eastern (MID) AF: 0.0485 AC: 279 AN: 5758

European-Non Finnish (NFE) AF: 0.0223 AC: 24815 AN: 1111374

Other (OTH) AF: 0.0172 AC: 1037 AN: 60340

GnomAD4 genome AF: 0.0173 AC: 2633 AN: 151962 Hom.: 35 Cov.: 32 AF XY: 0.0181 AC XY: 1347 AN XY: 74240

African (AFR) AF: 0.00427 AC: 177 AN: 41472

American (AMR) AF: 0.0177 AC: 269 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4820

European-Finnish (FIN) AF: 0.0437 AC: 460 AN: 10516

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1572 AN: 67968

Other (OTH) AF: 0.0199 AC: 42 AN: 2110

Alfa AF: 0.0199 Hom.: 82

Bravo AF: 0.0153

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0223 AC: 86

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0243 AC: 209

ExAC AF: 0.0177 AC: 2150

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Dec 12, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PKHD1 c.11525G>T (p.Arg3842Leu) variant causes a missense change involving a non-conserved nucleotide, which in silico tools predict conflicting results, 2/4 predict "benign" and 2/4 predict "damaging." This variant was found in 2160/121714 control chromosomes (including 21 homozygotes) at a frequency of 0.0177465, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this variant is likely a benign polymorphism. The variant is more common in European subpopulations from ExAC with allele frequencies of 3-4%. In literature, the variant has also been reported as a polymorphism or a benign variant found in ARPKD patients (Bergmann_2005, Sharp_2005, Gunay-Aygun_2010). In addition, multiple clinical diagnostic laboratories have classified this variant as benign. Taken together, this variant is classified as Benign. -

Oct 20, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15698423, 19914852) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKHD1: BS1, BS2 -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

Jul 15, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive polycystic kidney disease Benign:3

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Arg3842Leu variant was identified in 8 of 636 proband chromosomes (frequency: 0.01) from European, Dutch and American individuals or families with ARPKD and was present in 11 of 600 control chromosomes (frequency: 0.02) from healthy individuals (Sharp_2005_15805161, Losekoot_2005_16133180, Gunay-Aygun_2010_19914852, Bergmann_2005_15698423). The variant was also identified in the following databases: dbSNP (ID: rs76572975) “With Benign allele”, ClinVar (benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Prevention Genetics and Invitae), RWTH AAachen University ARPKD database, and was not identified in the COGR and LOVD 3.0. The variant was identified in control databases in 5207 (73 homozygous) of 276514 chromosomes at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 77 of 24014 chromosomes (freq: 0.003), Other in 113 (2 homozygous) of 6444 chromosomes (freq: 0.02), Latino in 402 (4 homozygous) of 34320 chromosomes (freq: 0.01), European Non-Finnish in 3049 (41 homozygous) of 126226 chromosomes (freq: 0.02), Ashkenazi Jewish in 241 (3 homozygous) of 10130 chromosomes (freq: 0.02), European Finnish in 1066 (23 homozygous) of 25770 chromosomes (freq: 0.04), and South Asian in 259 of 30778 chromosomes (freq: 0.008); it was not observed in the East Asian populations. The p.Arg3842 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Leu to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.50
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0077	T
MetaSVM	Uncertain	-0.0021	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.32
Sift	Benign	0.12	T
Sift4G	Benign	1.0	T
Polyphen		0.99	D
Vest4		0.13
MPC		0.12
ClinPred		0.037	T
GERP RS		5.7
Varity_R		0.18
gMVP		0.50
Mutation Taster		=76/24	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76572975; hg19: chr6-51497503; COSMIC: COSV64386744;