6-51748201-C-A

Position:

chr6-51748201-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_138694.4(PKHD1):c.9415G>T(p.Asp3139Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00566 in 1,614,030 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.0039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 20 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: 0.745

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008653432).

BP6

Variant 6-51748201-C-A is Benign according to our data. Variant chr6-51748201-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167479.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=1, Benign=3}. Variant chr6-51748201-C-A is described in Lovd as [Likely_benign]. Variant chr6-51748201-C-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.9415G>T	p.Asp3139Tyr	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.9415G>T	p.Asp3139Tyr	missense_variant	58/67	1	NM_138694.4	ENSP00000360158.3		P08F94-1
PKHD1	ENST00000340994.4 linkuse as main transcript	c.9415G>T	p.Asp3139Tyr	missense_variant	58/61	5		ENSP00000341097.4		P08F94-2

Frequencies

GnomAD3 genomes

AF:

0.00395

AC:

601

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00810

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00629

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00415

AC:

1041

AN:

250812

Hom.:

AF XY:

0.00447

AC XY:

606

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.000895

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00301

Gnomad FIN exome

AF:

0.00753

Gnomad NFE exome

AF:

0.00621

Gnomad OTH exome

AF:

0.00409

GnomAD4 exome

AF:

0.00583

AC:

8528

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00575

AC XY:

4180

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.000651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00326

Gnomad4 FIN exome

AF:

0.00629

Gnomad4 NFE exome

AF:

0.00675

Gnomad4 OTH exome

AF:

0.00495

GnomAD4 genome

AF:

0.00395

AC:

601

AN:

152252

Hom.:

Cov.:

AF XY:

0.00392

AC XY:

292

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00144

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00810

Gnomad4 NFE

AF:

0.00629

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00532

Hom.:

Bravo

AF:

0.00301

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00418

AC:

508

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease

Uncertain:1Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Aug 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Feb 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 09, 2014	- -
Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Sep 04, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 23, 2017	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 14, 2019	Variant summary: PKHD1 c.9415G>T (p.Asp3139Tyr) results in a non-conservative amino acid change located in the right handed beta helix domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0041 in 277424 control chromosomes, predominantly at a frequency of 0.0075 within the Finnish subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 1.061 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 found primarily in populations of Finnish origin. c.9415G>T has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease (Bergmann_2005, Furu_2003, Gunay-Aygun_2010, Losekoot_2005, Onuchi_2002, rossetti_2003, Ward_2002), however, authors predominantly refer to the variant as a polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PKHD1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2020	This variant is associated with the following publications: (PMID: 12874454, 26990548, 11898128, 21228398) -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKHD1 p.Asp3139Tyr variant was identified in 6 of 888 proband chromosomes (frequency: 0.007) from individuals or families with ARPKD and was present in 13 of 1440 control chromosomes (frequency: 0.009) from healthy individuals (Bergmann 2004, Bergmann 2005, Gunay-Aygun 2010, Losekoot 2005, Rosetti 2003, Sharp 2005). The variant was also identified in dbSNP (ID: rs45503297) as "With other allele", ClinVar (classified as benign by Invitae; and as likely benign by Prevention Genetics, Counsyl, and three other submitters), LOVD 3.0 (4x as likely benign), and in RWTH AAachen University ARPKD database (as polymorphism). The variant was identified in control databases in 1133 of 276504 chromosomes (4 homozygous) at a frequency of 0.004, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 27 of 24022 chromosomes (freq: 0.001), Other in 19 of 6456 chromosomes (freq: 0.003), Latino in 34 of 34376 chromosomes (freq: 0.0009), European in 757 of 126108 chromosomes (freq: 0.006), Ashkenazi Jewish in 9 of 10126 chromosomes (freq: 0.001), Finnish in 193 of 25786 chromosomes (freq: 0.007), and South Asian in 94 of 30780 chromosomes (freq: 0.003), while the variant was not observed in the East Asian population. The p.Asp3139 residue is not 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Polycystic kidney disease 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.46

T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.0087

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.7

L;L

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.17

Sift

Benign

1.0

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.0070

B;B

Vest4

0.26

MVP

0.92

MPC

0.078

ClinPred

0.0062

GERP RS

2.9

Varity_R

0.034

gMVP

0.79

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