rs142522748

Positions:

chr6-51772738-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_138694.4(PKHD1):c.8606C>A(p.Thr2869Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0117 in 1,597,930 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts 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. T2869T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 31)

Exomes 𝑓: 0.012 ( 152 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.54

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020076126).

BP6

Variant 6-51772738-G-T is Benign according to our data. Variant chr6-51772738-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 96436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51772738-G-T is described in Lovd as [Likely_pathogenic]. Variant chr6-51772738-G-T is described in Lovd as [Benign]. Variant chr6-51772738-G-T is described in Lovd as [Likely_benign]. Variant chr6-51772738-G-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1548/151964) while in subpopulation NFE AF= 0.0164 (1114/67924). AF 95% confidence interval is 0.0156. There are 11 homozygotes in gnomad4. There are 704 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.8606C>A	p.Thr2869Lys	missense_variant	55/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.8606C>A	p.Thr2869Lys	missense_variant	55/67	1	NM_138694.4	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.8606C>A	p.Thr2869Lys	missense_variant	55/61	5		A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1547

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00849

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00945

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.0164

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00927

AC:

2325

AN:

250704

Hom.:

AF XY:

0.00908

AC XY:

1230

AN XY:

135496

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00642

Gnomad ASJ exome

AF:

0.0150

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000850

Gnomad FIN exome

AF:

0.00924

Gnomad NFE exome

AF:

0.0144

Gnomad OTH exome

AF:

0.0111

GnomAD4 exome

AF:

0.0118

AC:

17087

AN:

1445966

Hom.:

152

Cov.:

AF XY:

0.0118

AC XY:

8535

AN XY:

720306

show subpopulations

Gnomad4 AFR exome

AF:

0.00130

Gnomad4 AMR exome

AF:

0.00681

Gnomad4 ASJ exome

AF:

0.0150

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000791

Gnomad4 FIN exome

AF:

0.00908

Gnomad4 NFE exome

AF:

0.0138

Gnomad4 OTH exome

AF:

0.0109

GnomAD4 genome

AF:

0.0102

AC:

1548

AN:

151964

Hom.:

Cov.:

AF XY:

0.00948

AC XY:

704

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.00260

Gnomad4 AMR

AF:

0.00855

Gnomad4 ASJ

AF:

0.0187

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00945

Gnomad4 NFE

AF:

0.0164

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0145

Hom.:

Bravo

AF:

0.00889

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0134

AC:

115

ExAC

AF:

0.00930

AC:

1129

Asia WGS

AF:

0.000867

AC:

AN:

3476

EpiCase

AF:

0.0138

EpiControl

AF:

0.0123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Mar 27, 2014	- -
Likely benign, 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). 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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. -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PKHD1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 22, 2016	Variant summary: c.8606C>A affects a conserved nucleotide, resulting in amino acid change from Thr to Lys. 3/4 in-silico tools predict this variant to be damaging, however, these in silico predictions have not been validated by any in vitro/vivo functional studies yet. This variant was found in 1133/121106 control chromosomes at a frequency of 0.0093554, predominantly observed in non-Finnish European subpopulation in ExAC with MAF of 0.01445 (962/66572 chr) with total 14 homozygotes. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0070711), suggesting this variant is a benign polymorphism in non-Finnish Europeans. Two clinical laboratories via ClinVar classified this variant as benign/likely benign. Autosomal Recessive Polycystic Kidney Disease database and multiple literature publications list this variant as polymorphism. Considering all, this variant was classified as Likely Benign until more information becomes available. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 2020	This variant is associated with the following publications: (PMID: 12874454, 15108277, 15805161, 15698423, 28492530, 12846734, 16133180, 25701400) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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.Thr2869Lys variant was identified in 5 of 122 proband chromosomes (frequency: 0.041) from Spanish, American and British individuals or families with ARPKD/congenital hepatic fibrosis/Caroliâ€šÃ„Ã´s disease, and was present in 5 of 420 control chromosomes (frequency: 0.012) from healthy individuals (Rosetti 2003, Furu 2004, Sharp 2005). Kindreds in which the variant was identified also carried multiple other variants, with at least one being pathogenic (Rosetti 2003). The variant was also identified in dbSNP (ID: rs142522748) â€šÃ„ÃºWith likely benign alleleâ€šÃ„Ã¹, Clinvitae database (classifications benign/likely benign), the ClinVar database (classification benign by Emory Genetics Laboratory, and likely benign by Counsyl), RWTH AAachen University ARPKD database (classified as a polymorphism) and PKHD1-LOVD (not classified); in the 1000 Genomes Project in 21 of 5000 chromosomes (frequency: 0.0042), HAPMAP populations EUR in 9 of 1006 chromosomes (frequency: 0.0089) and AMR in 12 of 694 chromosomes (frequency: 0.0173), NHLBI GO Exome Sequencing Project in 115 of 8600 European American alleles (frequency: 0.0134) and in 8 of 4406 African American alleles (frequency: 0.0018), and in the Exome Aggregation Consortium database (March 14, 2016) in 976 of 66572 chromosomes (frequency: 0.0145) from a population of European (Non-Finnish) individuals, and none in the East Asian, Other, African, Latino, South Asian, or European (Finnish) populations. The p.Thr2869 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as likely benign. -

Caroli disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

D;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.020

T;T

MetaSVM

Uncertain

0.62

MutationAssessor

Pathogenic

3.2

M;M

MutationTaster

Benign

0.93

N;N

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-4.3

D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.98

D;D

Vest4

0.84

MVP

0.99

MPC

0.40

ClinPred

0.035

GERP RS

4.9

Varity_R

0.82

gMVP

0.95

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over