rs201432731

chr6-52050242-C-Achr6-52050242-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_138694.4(PKHD1):c.2194G>T(p.Val732Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,614,220 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V732V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 0.0430

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_138694.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.009299189).
• BP6: Variant 6-52050242-C-A is Benign according to our data. Variant chr6-52050242-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288720.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=2, Likely_benign=1}. Variant chr6-52050242-C-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.2194G>T	p.Val732Phe	missense_variant	22/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.2194G>T	p.Val732Phe	missense_variant	22/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.2194G>T	p.Val732Phe	missense_variant	22/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152252 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000784 AC: 197 AN: 251218 Hom.: 1 AF XY: 0.000700 AC XY: 95 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000350 AC: 512 AN: 1461850 Hom.: 3 Cov.: 34 AF XY: 0.000333 AC XY: 242 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.0120

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.000564 AC: 86 AN: 152370 Hom.: 2 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74510

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000759

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000527 AC: 64

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 09, 2017	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic in patients with PKHD1-related disease to our knowledge; This variant is associated with the following publications: (PMID: 12874454) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2016	- -

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2021

This variant is classified as 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	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0093	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Benign	0.22
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.88	P;P
Vest4		0.35
MVP		0.97
MPC		0.24
ClinPred		0.068	T
GERP RS		1.9
Varity_R		0.19
gMVP		0.55

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: rs201432731; hg19: chr6-51915040;