rs41273726

Variant names:

• chr6-52028309-T-C
• rs41273726
• NM_138694.4:c.3407A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-52028309-T-C
• chr6-52028309-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_138694.4(PKHD1):​c.3407A>G​(p.Tyr1136Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00846 in 1,614,058 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. Y1136N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0084 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (103 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:14
• Conservation: PhyloP100: -0.0580
• Publications: 21 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010802239).
• BP6: Variant 6-52028309-T-C is Benign according to our data. Variant chr6-52028309-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167489.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00842 (1282/152242) while in subpopulation NFE AF = 0.014 (955/68004). AF 95% confidence interval is 0.0133. There are 11 homozygotes in GnomAd4. There are 587 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.3407A>G	p.Tyr1136Cys	missense_variant	Exon 30 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.3407A>G	p.Tyr1136Cys	missense_variant	Exon 30 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.3407A>G	p.Tyr1136Cys	missense_variant	Exon 30 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00843 AC: 1282 AN: 152124 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00764 AC: 1921 AN: 251458 AF XY: 0.00737

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00846 AC: 12371 AN: 1461816 Hom.: 103 Cov.: 31 AF XY: 0.00865 AC XY: 6289 AN XY: 727218

African (AFR) AF: 0.00105 AC: 35 AN: 33480

American (AMR) AF: 0.00157 AC: 70 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 422 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00243 AC: 210 AN: 86256

European-Finnish (FIN) AF: 0.0127 AC: 678 AN: 53420

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5720

European-Non Finnish (NFE) AF: 0.00949 AC: 10550 AN: 1111992

Other (OTH) AF: 0.00669 AC: 404 AN: 60388

GnomAD4 genome AF: 0.00842 AC: 1282 AN: 152242 Hom.: 11 Cov.: 32 AF XY: 0.00789 AC XY: 587 AN XY: 74436

African (AFR) AF: 0.00132 AC: 55 AN: 41542

American (AMR) AF: 0.00248 AC: 38 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.0127 AC: 135 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0140 AC: 955 AN: 68004

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.0117 Hom.: 56

Bravo AF: 0.00606

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00790 AC: 959

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.00771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 30, 2014

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 28, 2017

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 12, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:5

Jun 19, 2017

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: The PKHD1 c.3407A>G (p.Tyr1136Cys) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not available). This variant was found in 960/121796 control chromosomes (14 homozygotes) at a frequency of 0.007882, which slightly exceeds the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this variant is likely a benign polymorphism. In the literature this variant was reported in multiple patients with ARPKD without strong evidence for causality. One reported patient had co-occurrence of a pathogenic variant PKHD1 c. 1458C>A, p.Tyr486X in cis, supporting the non-pathgoenic nature of the variant of interest (Gunay-Aygun_MGM_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as a likely benign. -

Feb 06, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKHD1: BP4, BS2 -

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 22, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30343465, 15805161, 21228398) -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Caroli disease Uncertain:1

May 05, 2021

Laboratory of Molecular Diagnosis of Genetic Disease, Università degli Studi di Napoli Federico II

Significance: Uncertain significance

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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKHD1 p.Tyr1136Cys variant was identified in 1 of 450 proband chromosomes (frequency: 0.002) from individuals or families with ARPKD, and was present in 1 of 400 control chromosomes (frequency: 0.0025) from healthy individuals (Bergmann_2005, Losekoot_2005). The variant was identified in dbSNP (ID: rs41273726) with “other” allele, in the 1000 Genomes Project in 13 of 5000 chromosomes (frequency: 0.0026) and in Exome Variant Server project in 88 of 8600 (frequency 0.01) in European American alleles and 3 of 4406 (frequency 0.0007) African American alleles. The variant was also identified in the Exome Aggregation Consortium database (March 14, 2016) in 959 of 121396 chromosomes of which 14 are homozygotes (frequency 0.0079); or 80 of 6612 European Finnish (frequency 0.0121), 797 of 66734 European non Finnish (frequency 0.01194), 37 of 16512 south Asians (frequency 0.002241), 22 of 11576 Latino (frequency 0.0019), 15 of 10404 African (frequency 0.01442), 1 of 8650 East Asians (frequency 0.0001) and 7 of 908 other (frequency 0.008). The variant was also listed in ClinVar 1x by Emory Genetics Laboratory and 1x by Invitae as benign and identified by Counsyl 1x as likely benign and in Clinvitae by EmyClass 1x as benign. The variant was also identified in RWTH AAachen University ARPKD database with conflicting interpretations: 6x as polymorphism, 11x as pathogenic and 13x as probably pathogenic with control frequency of 0% - 0.5%. The p.Tyr1136 residue is not entirely conserved in mammals and the variant amino acid Cystine is present in frog and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In addition this variant was seen co-occurring with a pathogenic variant (c.8095C>T, p.Gln2699X) in a patient with polycystic kidney disease. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of likely benign. -

Polycystic kidney disease 4 Benign:1

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.5
DANN	Benign	0.94
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		-0.058
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Benign	0.21
Sift	Benign	0.11	T;T
Sift4G	Uncertain	0.055	T;T
Polyphen		1.0	D;D
Vest4		0.38
MVP		0.91
MPC		0.075
ClinPred		0.050	T
GERP RS		0.46
Varity_R		0.12
gMVP		0.51
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs41273726; hg19: chr6-51893107; COSMIC: COSV61870616;