rs41273726

chr6-52028309-T-Cchr6-52028309-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 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. 13/19 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

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 Benign. Variant got -9 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 id is 167489.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=4, Uncertain_significance=2}. Variant chr6-52028309-T-C is described in Lovd as [Likely_benign]. Variant chr6-52028309-T-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.3407A>G	p.Tyr1136Cys	missense_variant	30/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.3407A>G	p.Tyr1136Cys	missense_variant	30/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.3407A>G	p.Tyr1136Cys	missense_variant	30/61	5		A2

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

GnomAD3 exomes AF: 0.00764 AC: 1921 AN: 251458 Hom.: 26 AF XY: 0.00737 AC XY: 1002 AN XY: 135898

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 SAS exome AF: 0.00238

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

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00243

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.00949

Gnomad4 OTH exome AF: 0.00669

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

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0115 Hom.: 29

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

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 28, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 12, 2016	- -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2020	This variant is associated with the following publications: (PMID: 30343465, 15805161, 21228398) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PKHD1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 06, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2017	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. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Caroli disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 05, 2021

- -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

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
MutationTaster	Benign	1.0	N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs41273726; hg19: chr6-51893107; COSMIC: COSV61870616;