rs2435322

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_138694.4(PKHD1):c.5608T>G(p.Leu1870Val) variant causes a missense change. The variant allele was found at a frequency of 0.993 in 1,597,222 control chromosomes in the GnomAD database, including 787,696 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.96 ( 70599 hom., cov: 30)

Exomes 𝑓: 1.0 ( 717097 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.28

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=5.6595013E-7).

BP6

Variant 6-52010452-A-C is Benign according to our data. Variant chr6-52010452-A-C is described in ClinVar as [Benign]. Clinvar id is 96410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52010452-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.5608T>G	p.Leu1870Val	missense_variant	35/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8 linkuse as main transcript	c.5608T>G	p.Leu1870Val	missense_variant	35/67	1	NM_138694.4	ENSP00000360158	P2	P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.5608T>G	p.Leu1870Val	missense_variant	35/61	5		ENSP00000341097	A2	P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.961

AC:

146193

AN:

152086

Hom.:

70555

Cov.:

show subpopulations

Gnomad AFR

AF:

0.865

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.986

Gnomad ASJ

AF:

0.999

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.974

GnomAD3 exomes

AF:

0.990

AC:

248675

AN:

251296

Hom.:

123198

AF XY:

0.993

AC XY:

134829

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.858

Gnomad AMR exome

AF:

0.993

Gnomad ASJ exome

AF:

0.999

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.995

GnomAD4 exome

AF:

0.996

AC:

1439260

AN:

1445018

Hom.:

717097

Cov.:

AF XY:

0.997

AC XY:

717668

AN XY:

720126

show subpopulations

Gnomad4 AFR exome

AF:

0.860

Gnomad4 AMR exome

AF:

0.993

Gnomad4 ASJ exome

AF:

0.999

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

1.00

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

1.00

Gnomad4 OTH exome

AF:

0.991

GnomAD4 genome

AF:

0.961

AC:

146293

AN:

152204

Hom.:

70599

Cov.:

AF XY:

0.963

AC XY:

71696

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.865

Gnomad4 AMR

AF:

0.986

Gnomad4 ASJ

AF:

0.999

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

1.00

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

1.00

Gnomad4 OTH

AF:

0.974

Alfa

AF:

0.991

Hom.:

117391

Bravo

AF:

0.955

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

0.999

AC:

3852

ESP6500AA

AF:

0.866

AC:

3814

ESP6500EA

AF:

0.999

AC:

8592

ExAC

AF:

0.987

AC:

119853

Asia WGS

AF:

0.993

AC:

3453

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Benign:4

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	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -

Polycystic kidney disease 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 19, 2021	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKHD1 p.Leu1870Val variant was identified in RWTH AAachen University ARPKD database as a polymorphism, noting the variant is c.5608G>T (current reference base T), p.Val1870Leu (current reference amino acid Leu), and in control databases in 3683 of 277008 chromosomes at a frequency of 0.0133 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 3337 of 24020 chromosomes (freq: 0.1389), Other in 38 of 6468 chromosomes (freq: .0059), Latino in 234 of 34402 chromosomes (freq: .0068), European Non-Finnish in 56 of 126528 chromosomes (freq: .0004), Ashkenazi Jewish in 10 of 10148 chromosomes (freq: .001), East Asian in 1 of 18868 chromosomes (freq: 0.0001), and South Asian in 7 of 30782 chromosomes (freq: 0.0002), while not observed in the European Finnish population. The previously recognized PKHD1 p.Leu1870Val variant was identified dbSNP (ID: rs2435322) â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar (classified benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Prevention Genetics, Illumina), Clinvitae (3x), and was not identified in the literature or LOVD 3.0. The previously recognized p.Leu1870 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of Val impacting the protein; however, this information is not predictive enough to rule out 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 this variant meets our laboratory criteria to be classified as benign. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

This variant is associated with the following publications: (PMID: 28509106) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.029

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.16

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.37

T;T

MetaRNN

Benign

5.7e-7

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.0

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.56

PROVEAN

Benign

1.8

N;N

REVEL

Uncertain

0.34

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.037

MPC

0.060

ClinPred

0.010

GERP RS

5.6

Varity_R

0.092

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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