rs372340268

chr6-52064997-G-Achr6-52064997-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_138694.4(PKHD1):c.934C>T(p.Arg312Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,604,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R312Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000094 ( 0 hom., cov: 23)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.12

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_138694.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.934C>T	p.Arg312Trp	missense_variant	13/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.934C>T	p.Arg312Trp	missense_variant	13/67	1	NM_138694.4	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.934C>T	p.Arg312Trp	missense_variant	13/61	5		A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.0000944

AC:

AN:

148348

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000757

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000217

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

250844

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000884

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000136

AC:

198

AN:

1455784

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

101

AN XY:

724414

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000395

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000138

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.0000944

AC:

AN:

148348

Hom.:

Cov.:

AF XY:

0.0000831

AC XY:

AN XY:

72174

show subpopulations

Gnomad4 AFR

AF:

0.0000757

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000217

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 28, 2021	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 312 of the PKHD1 protein (p.Arg312Trp). This variant is present in population databases (rs372340268, gnomAD 0.06%). This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 33123899). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 502343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PKHD1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 16, 2017	- -

Polycystic kidney disease

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKHD1 p.Arg312Trp variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, or the RWTH AAachen University ARPKD database. The identification of this variant in one individual by our laboratory with ARPKD and a co-occurring pathogenic variant in ARPKD, increases the likelihood, this variant may have clinical significance. The variant was identified in dbSNP (ID: rs372340268) as â€šÃ„ÃºNAâ€šÃ„Ã¹, and in control databases in 33 of 275364 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 2 of 23724 chromosomes (freq: 0.00008), European Non-Finnish in 11 of 125766 chromosomes (freq: 0.00009), and South Asian in 20 of 30782 chromosomes (freq: 0.0007) and was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Arg312 residue is conserved in mammals 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. 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 the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 29, 2018

- -

PKHD1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2024

The PKHD1 c.934C>T variant is predicted to result in the amino acid substitution p.Arg312Trp. This variant was reported with a deletion affecting exons 12-13 of PKHD1 in an individual with hepatic fibrosis and normal renal function (Qiu et al. 2020. PubMed ID: 33123899). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Polycystic kidney disease 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.16

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.74

T;T

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.50

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

0.93

N;N

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.3

D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.49

MVP

0.94

MPC

0.38

ClinPred

0.76

GERP RS

2.1

Varity_R

0.39

gMVP

0.60

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

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