6-51632705-C-A

Position:

chr6-51632705-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_138694.4(PKHD1):c.11525G>T(p.Arg3842Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,612,948 control chromosomes in the GnomAD database, including 441 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 0.017 ( 35 hom., cov: 32)

Exomes 𝑓: 0.021 ( 406 hom. )

Consequence

PKHD1
NM_138694.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.69

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=0.0076598525).

BP6

Variant 6-51632705-C-A is Benign according to our data. Variant chr6-51632705-C-A is described in ClinVar as [Benign]. Clinvar id is 96371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51632705-C-A is described in Lovd as [Benign]. Variant chr6-51632705-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0173 (2633/151962) while in subpopulation NFE AF= 0.0231 (1572/67968). AF 95% confidence interval is 0.0222. There are 35 homozygotes in gnomad4. There are 1347 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4 linkuse as main transcript	c.11525G>T	p.Arg3842Leu	missense_variant	65/67	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.11525G>T	p.Arg3842Leu	missense_variant	65/67	1	NM_138694.4	ENSP00000360158.3		P08F94-1

Frequencies

GnomAD3 genomes

AF:

0.0174

AC:

2636

AN:

151844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00423

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.0437

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0231

Gnomad OTH

AF:

0.0201

GnomAD3 exomes

AF:

0.0189

AC:

4729

AN:

250844

Hom.:

AF XY:

0.0192

AC XY:

2609

AN XY:

135558

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0237

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00830

Gnomad FIN exome

AF:

0.0416

Gnomad NFE exome

AF:

0.0245

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0207

AC:

30239

AN:

1460986

Hom.:

406

Cov.:

AF XY:

0.0207

AC XY:

15058

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.00472

Gnomad4 AMR exome

AF:

0.0123

Gnomad4 ASJ exome

AF:

0.0230

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00899

Gnomad4 FIN exome

AF:

0.0378

Gnomad4 NFE exome

AF:

0.0223

Gnomad4 OTH exome

AF:

0.0172

GnomAD4 genome

AF:

0.0173

AC:

2633

AN:

151962

Hom.:

Cov.:

AF XY:

0.0181

AC XY:

1347

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.00427

Gnomad4 AMR

AF:

0.0177

Gnomad4 ASJ

AF:

0.0182

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00664

Gnomad4 FIN

AF:

0.0437

Gnomad4 NFE

AF:

0.0231

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.0208

Hom.:

Bravo

AF:

0.0153

TwinsUK

AF:

0.0227

AC:

ALSPAC

AF:

0.0223

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0243

AC:

209

ExAC

AF:

0.0177

AC:

2150

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2013	- -

Autosomal recessive polycystic kidney disease

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2016	Variant summary: The PKHD1 c.11525G>T (p.Arg3842Leu) variant causes a missense change involving a non-conserved nucleotide, which in silico tools predict conflicting results, 2/4 predict "benign" and 2/4 predict "damaging." This variant was found in 2160/121714 control chromosomes (including 21 homozygotes) at a frequency of 0.0177465, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this variant is likely a benign polymorphism. The variant is more common in European subpopulations from ExAC with allele frequencies of 3-4%. In literature, the variant has also been reported as a polymorphism or a benign variant found in ARPKD patients (Bergmann_2005, Sharp_2005, Gunay-Aygun_2010). In addition, multiple clinical diagnostic laboratories have classified this variant as benign. Taken together, this variant is classified as Benign. -
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	GeneDx	Oct 20, 2020	This variant is associated with the following publications: (PMID: 15698423, 19914852) -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKHD1 p.Arg3842Leu variant was identified in 8 of 636 proband chromosomes (frequency: 0.01) from European, Dutch and American individuals or families with ARPKD and was present in 11 of 600 control chromosomes (frequency: 0.02) from healthy individuals (Sharp_2005_15805161, Losekoot_2005_16133180, Gunay-Aygun_2010_19914852, Bergmann_2005_15698423). The variant was also identified in the following databases: dbSNP (ID: rs76572975) â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, ClinVar (benign by EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), Prevention Genetics and Invitae), RWTH AAachen University ARPKD database, and was not identified in the COGR and LOVD 3.0. The variant was identified in control databases in 5207 (73 homozygous) of 276514 chromosomes at a frequency of 0.02 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 77 of 24014 chromosomes (freq: 0.003), Other in 113 (2 homozygous) of 6444 chromosomes (freq: 0.02), Latino in 402 (4 homozygous) of 34320 chromosomes (freq: 0.01), European Non-Finnish in 3049 (41 homozygous) of 126226 chromosomes (freq: 0.02), Ashkenazi Jewish in 241 (3 homozygous) of 10130 chromosomes (freq: 0.02), European Finnish in 1066 (23 homozygous) of 25770 chromosomes (freq: 0.04), and South Asian in 259 of 30778 chromosomes (freq: 0.008); it was not observed in the East Asian populations. The p.Arg3842 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Leu 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 this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.50

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0077

MetaSVM

Uncertain

-0.0021

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.32

Sift

Benign

0.12

Sift4G

Benign

1.0

Polyphen

0.99

Vest4

0.13

MPC

0.12

ClinPred

0.037

GERP RS

5.7

Varity_R

0.18

gMVP

0.50

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