rs201906247

chr6-52017600-G-Achr6-52017600-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138694.4(PKHD1):c.5410C>T(p.Arg1804Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1804H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.706

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01556766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.5410C>T	p.Arg1804Cys	missense_variant	34/67	ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.5410C>T	p.Arg1804Cys	missense_variant	34/67	1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.5410C>T	p.Arg1804Cys	missense_variant	34/61	5		A2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000231 AC: 58 AN: 250692 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135516

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000196 AC: 286 AN: 1461474 Hom.: 0 Cov.: 32 AF XY: 0.000219 AC XY: 159 AN XY: 727042

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000673

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74426

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000167 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 05, 2021	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1804 of the PKHD1 protein (p.Arg1804Cys). This variant is present in population databases (rs201906247, gnomAD 0.08%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15805161). ClinVar contains an entry for this variant (Variation ID: 501154). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PKHD1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	Identified in a patient with ARPKD with a second variant in an unknown phase in published literature (Sharp et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15805161) -

PKHD1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 24, 2022

The PKHD1 c.5410C>T variant is predicted to result in the amino acid substitution p.Arg1804Cys. This variant has been reported with a canonical splice variant (c.5381-2A>C) in a fetal specimen due to suspected autosomal recessive polycystic kidney disease (ARPKD) (Sharp et al. 2005. PubMed ID: 15805161). This variant was also described in a large cohort of individuals with suspected early-onset chronic kidney disease (Domingo-Gallego et al. 2022. PubMed ID: 33532864, supplementary data). This variant is reported in 0.078% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51882398-G-A). This variant could be pathogenic. At this time, however, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	14
Dann	Uncertain	0.98
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.16
Sift	Benign	0.067	T;T
Sift4G	Benign	0.076	T;T
Polyphen		0.28	B;B
Vest4		0.18
MutPred		0.52		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.75
MPC		0.15
ClinPred		0.018	T
GERP RS		1.6
Varity_R		0.057
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs201906247; hg19: chr6-51882398; COSMIC: COSV61887081;