rs145651593

Positions:

chr6-51748063-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138694.4(PKHD1):c.9553G>A(p.Val3185Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 0.0820

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:

PKHD1 (HGNC:):

PKHD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0071715415).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.9553G>A	p.Val3185Ile	missense_variant	58/67	ENST00000371117.8	NP_619639.3	P08F94-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.9553G>A	p.Val3185Ile	missense_variant	58/67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.9553G>A	p.Val3185Ile	missense_variant	58/61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

250862

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135538

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000739

AC:

108

AN:

1461776

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000611

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00217

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.000759

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000272

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2022	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PKHD1: PM2, BP4 -

Autosomal recessive polycystic kidney disease

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 11, 2017

Variant summary: The c.9553G>A (p.Val3185Ile) in PKHD1 gene is a missense variant involves a non-conserved nucleotide located outside of any known functional domain or repeat. The 4/4 in silico tools used predict benign outcome for this variant, however no functional studies supporting these predictions were published at the time of evaluation. The c. 9553G>A was identified in the control population dataset of gnomAD at a low frequency of 0.00024 (69/276536 chrs tested), predominantly in individuals of African descent (0.0027; 64/24022 chrs). The observed frequencies do not exceed the maximum expected allele frequency for a pathogenic variant of 0.007, suggesting that it is not a common polymorphism. To our knowledge, the variant has not been reported in affected individuals via peer-reviewed reports or cited by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.9553G>A (p.V3185I) alteration is located in exon 58 (coding exon 57) of the PKHD1 gene. This alteration results from a G to A substitution at nucleotide position 9553, causing the valine (V) at amino acid position 3185 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PKHD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 12, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.0072

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.64

N;N

REVEL

Benign

0.099

Sift

Benign

0.072

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.085

B;B

Vest4

0.21

MVP

0.74

MPC

0.074

ClinPred

0.013

GERP RS

3.0

Varity_R

0.058

gMVP

0.32

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