rs146519878

Positions:

• chr6-51747828-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138694.4(PKHD1):​c.9788T>C​(p.Val3263Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,613,826 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (10 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 3.40

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064140856).
• BP6: Variant 6-51747828-A-G is Benign according to our data. Variant chr6-51747828-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167477.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=1}. Variant chr6-51747828-A-G is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.9788T>C	p.Val3263Ala	missense_variant	58/67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.9788T>C	p.Val3263Ala	missense_variant	58/67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.9788T>C	p.Val3263Ala	missense_variant	58/61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 378 AN: 152100 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00167 AC: 420 AN: 251166 Hom.: 1 AF XY: 0.00168 AC XY: 228 AN XY: 135738

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00306 AC: 4468 AN: 1461608 Hom.: 10 Cov.: 33 AF XY: 0.00298 AC XY: 2168 AN XY: 727120

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.000985

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.00378

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152218 Hom.: 4 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74414

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00293 Hom.: 4

Bravo AF: 0.00290

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00173 AC: 210

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00332

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 16, 2017	Variant summary: The PKHD1 c.9788T>C (p.Val3263Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 463/258028 control chromosomes (gnomAD), including 2 homozygotes, at a frequency of 0.0017944, which does not exceed the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711). Clinical diagnostic laboratories/reputable databases classified this variant as likely benign and uncertain significance. The variant of interest has been reported in multiple patients with ARPKD (Melchionda_2016, Sharp_2005) and pathologies with partially overlapping renal phenotype, including one patient with dominantly inherited isolated polycystic liver disease (Besse_2017), all without strong evidence for causality. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until more definitive clinical and functional data become available. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2016	- -

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PKHD1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2020	This variant is associated with the following publications: (PMID: 21228398, 15805161) -

Polycystic kidney disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKHD1, p.Val3263Ala variant was identified in 2 of 274 proband chromosomes (frequency: 0.007) from individuals or families with ARPKD, and was not identified in 200 control chromosomes from healthy individuals (Sharp 2005, Gunay-Aygun 2010). The variant was also identified in dbSNP (ID: rs146519878) as “With Uncertain significance allele”, Clinvitae database (classified as unclassified variant by ClinVar and Invitae), the ClinVar database (classified as uncertain significance by Emory Genetics and Invitae), RWTH AAachen University ARPKD database (classified as probably benign) and PKHD1-LOVD (2x as unknown/not classified). This variant was identified in the 1000 Genomes Project in 6 of 5000 chromosomes (frequency: 0.0012), the NHLBI GO Exome Sequencing Project in 25 of 8600 European American and in 1 of 4406 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 210 (1 homozygous) of 121276 chromosomes (freq. 0.002) in the following populations: European in 193 of 66708 chromosomes (freq. 0.003), Latino in 7 of 11500 chromosomes (freq. 0.0006), African in 5 of 10406 chromosomes (freq. 0.0005), Finnish in 3 of 6612 chromosomes (freq. 0.0005), South Asian in 1 of 16512 chromosomes (freq. 0.00006), Other in 1 of 906 chromosomes (freq. 0.001), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Val3263 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 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the loss of a 5’ splice site that is not at the canonical 5’ splice site. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Autosomal dominant polycystic liver disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

- -

PKHD1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 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	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.53	T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.18	T;T
Sift4G	Uncertain	0.014	D;D
Polyphen		0.91	P;P
Vest4		0.39
MVP		0.92
MPC		0.18
ClinPred		0.032	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.62

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

Other links and lift over

dbSNP: rs146519878; hg19: chr6-51612626; COSMIC: COSV99049429;