6-51659611-G-T

Position:

chr6-51659611-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_138694.4(PKHD1):c.10515C>A(p.Ser3505Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00972 in 1,613,614 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3505N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0070 ( 5 hom., cov: 32)

Exomes 𝑓: 0.010 ( 88 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.641

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0075244606).

BP6

Variant 6-51659611-G-T is Benign according to our data. Variant chr6-51659611-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 167474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51659611-G-T is described in Lovd as [Benign]. Variant chr6-51659611-G-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.10515C>A	p.Ser3505Arg	missense_variant	61/67	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.10515C>A	p.Ser3505Arg	missense_variant	61/67	1	NM_138694.4	ENSP00000360158.3		P08F94-1

Frequencies

GnomAD3 genomes

AF:

0.00696

AC:

1059

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00799

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00684

AC:

1710

AN:

250110

Hom.:

AF XY:

0.00658

AC XY:

889

AN XY:

135188

show subpopulations

Gnomad AFR exome

AF:

0.00216

Gnomad AMR exome

AF:

0.00595

Gnomad ASJ exome

AF:

0.00428

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00435

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.00854

GnomAD4 exome

AF:

0.0100

AC:

14630

AN:

1461440

Hom.:

Cov.:

AF XY:

0.00978

AC XY:

7112

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.00152

Gnomad4 AMR exome

AF:

0.00619

Gnomad4 ASJ exome

AF:

0.00471

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000394

Gnomad4 FIN exome

AF:

0.00489

Gnomad4 NFE exome

AF:

0.0121

Gnomad4 OTH exome

AF:

0.00792

GnomAD4 genome

AF:

0.00697

AC:

1060

AN:

152174

Hom.:

Cov.:

AF XY:

0.00636

AC XY:

473

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.00214

Gnomad4 AMR

AF:

0.00805

Gnomad4 ASJ

AF:

0.00548

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00424

Gnomad4 NFE

AF:

0.0113

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.0102

Hom.:

Bravo

AF:

0.00705

TwinsUK

AF:

0.0124

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0113

AC:

ExAC

AF:

0.00674

AC:

818

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0111

EpiControl

AF:

0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 05, 2019	Variant summary: PKHD1 c.10515C>A (p.Ser3505Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.007 in 281496 control chromosomes, predominantly at a frequency of 0.011 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism. Though the variant, c.10515C>A, has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease, it has also been found in controls, and therefore multiple studies reported it as a polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2014	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PKHD1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive polycystic kidney disease

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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. -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKHD1, p.Ser3505Arg variant was identified as a polymorphism in several studies (frequency information not specified) from Spanish, American and British individuals or families with ARPKD/congenital hepatic fibrosis/Caroliâ€šÃ„Ã´s disease, and was present in 6 of 390 control chromosomes (frequency: 0.015) from healthy individuals (Rosetti 2003, Sharp 2005, Losekoot 2005). The variant was also identified in dbSNP (ID: rs139014478) â€šÃ„ÃºWith benign alleleâ€šÃ„Ã¹, Clinvitae database (classification benign), the ClinVar database (classification benign by Emory Genetics Laboratory and Invitae), RWTH AAachen University ARPKD database (classified as a polymorphism); in the 1000 Genomes Project in 22 of 5000 chromosomes (frequency: 0.0044), HAPMAP populations EUR in 11 of 1006 chromosomes (frequency: 0.0109) and AMR in 11 of 694 chromosomes (frequency: 0.0159), NHLBI GO Exome Sequencing Project in 97 of 8600 European American alleles (frequency: 0.0112) and in 10 of 4406 African American alleles (frequency: 0.0022), and in the Exome Aggregation Consortium database (March 14m 2016) in 695 of 66390 chromosomes/ 5 homozygous (frequency: 0.0104) from a population of European (Non-Finnish) individuals, in 68 of 11398 chromosomes/ 1 homozygous (frequency: 0.0104) from a population of Latino individuals and none in the East Asian, Other, African, South Asian, or European (Finnish) populations. The p.Ser3505 residue is mostly 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. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.53

DEOGEN2

Benign

0.071

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0075

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

PrimateAI

Benign

0.34

PROVEAN

Benign

0.71

REVEL

Benign

0.15

Sift

Benign

0.71

Sift4G

Uncertain

0.0050

Polyphen

0.0060

Vest4

0.30

MutPred

0.34

Gain of catalytic residue at S3505 (P = 0.0082);

MVP

0.75

MPC

0.072

ClinPred

0.011

GERP RS

1.3

Varity_R

0.062

gMVP

0.70

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