4-88046642-G-T

Variant names:

• chr4-88046642-G-T
• rs886041114
• NM_000297.4:c.1320G>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000297.4(PKD2):​c.1320G>T​(p.Arg440Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000212 in 1,417,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PKD2 NM_000297.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.50

Genes affected

PKD2 (HGNC:9009): (polycystin 2, transient receptor potential cation channel) This gene encodes a member of the polycystin protein family. The encoded protein is a multi-pass membrane protein that functions as a calcium permeable cation channel, and is involved in calcium transport and calcium signaling in renal epithelial cells. This protein interacts with polycystin 1, and they may be partners in a common signaling cascade involved in tubular morphogenesis. Mutations in this gene are associated with autosomal dominant polycystic kidney disease type 2. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a topological_domain Extracellular (size 226) in uniprot entity PKD2_HUMAN there are 41 pathogenic changes around while only 9 benign (82%) in NM_000297.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-88046642-G-T is Pathogenic according to our data. Variant chr4-88046642-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 811865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88046642-G-T is described in Lovd as [Likely_pathogenic]. Variant chr4-88046642-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4	c.1320G>T	p.Arg440Ser	missense_variant, splice_region_variant	Exon 6 of 15	ENST00000237596.7	NP_000288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.1320G>T	p.Arg440Ser	missense_variant, splice_region_variant	Exon 6 of 15	1	NM_000297.4	ENSP00000237596.2
PKD2	ENST00000508588.5	c.-199+3185G>T		intron_variant	Intron 1 of 9	2		ENSP00000427131.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1417544 Hom.: 0 Cov.: 27 AF XY: 0.00000141 AC XY: 1 AN XY: 708166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000280

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease 2 Pathogenic:5

Feb 18, 2025

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD2 c.1320G>T (p.Arg440Ser) results in a non-conservative amino acid change located in the Polycystin domain (IPR046791) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a 5 donor site. Experimental evidence evaluating mRNA from patient leukocytes confirmed these predictions, showing the variant results in transcripts that skip exon 6 (Tan_2011). The variant was absent in 251286 control chromosomes (gnomAD). c.1320G>T has been reported in the literature in individuals affected with Polycystic Kidney Disease 2 (e.g. Tan_2011, Neumann_2012, Nielsen_2021, Lindemann_2022). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22367170, 33639313, 20950398, 36938073). ClinVar contains an entry for this variant (Variation ID: 811865). Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 24, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKD2 c.1320G>T; p.Arg440Ser variant is reported in the literature in several individuals affected with autosomal dominant polycystic kidney disease (Neumann 2012, Tan 2011). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in a moderately conserved nucleotide at the first nucleotide of exon 6, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical acceptor splice site. Consistent with these predictions, RNA analyses indicate increased skipping of exon 6 and decreased levels of mature PKD2 transcript in cells from an affected individual with this variant (Tan 2011). Based on available information, this variant is considered to be likely pathogenic. References: Neumann HP et al. Adult patients with sporadic polycystic kidney disease: the importance of screening for mutations in the PKD1 and PKD2 genes. Int Urol Nephrol. 2012 Dec;44(6):1753-62. Tan YC et al. Aberrant PKD2 splicing due to a presumed novel missense mutation in autosomal-dominant polycystic kidney disease. Clin Genet. 2011 Sep;80(3):287-92. -

Apr 05, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Aug 08, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is demonstrated to destroy the canonical splice acceptor site and result in loss of function (Tan et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26692149, 20950398, 22367170, 33639313) -

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD2: PM2, PS4:Moderate, PP3, PP4, PS3:Supporting -

Autosomal dominant polycystic kidney disease Pathogenic:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 440 of the PKD2 protein (p.Arg440Ser). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant polycystic kidney disease (PMID: 20950398, 23300259; internal data). ClinVar contains an entry for this variant (Variation ID: 811865). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in skipping of exon 6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20950398). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.39	B
Vest4		0.84
MutPred		0.71		Loss of methylation at R440 (P = 0.072);
MVP		0.88
MPC		0.61
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.67		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886041114; hg19: chr4-88967794;