rs145343957

chr4-88067950-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000297.4(PKD2):c.2411G>A(p.Ser804Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000532 in 1,614,094 control chromosomes in the GnomAD database, including 5 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 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: 9.31

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010641098).
• BP6: Variant 4-88067950-G-A is Benign according to our data. Variant chr4-88067950-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289403.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=4}. Variant chr4-88067950-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00263 (400/152294) while in subpopulation AFR AF= 0.00816 (339/41556). AF 95% confidence interval is 0.00744. There are 3 homozygotes in gnomad4. There are 208 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 400 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD2	NM_000297.4	c.2411G>A	p.Ser804Asn	missense_variant	13/15	ENST00000237596.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD2	ENST00000237596.7	c.2411G>A	p.Ser804Asn	missense_variant	13/15	1	NM_000297.4	P1

Frequencies

GnomAD3 genomes AF: 0.00263 AC: 400 AN: 152176 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00818

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.000848 AC: 213 AN: 251112 Hom.: 1 AF XY: 0.000737 AC XY: 100 AN XY: 135698

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000313 AC: 458 AN: 1461800 Hom.: 2 Cov.: 32 AF XY: 0.000296 AC XY: 215 AN XY: 727194

Gnomad4 AFR exome AF: 0.00624

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000827

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00263 AC: 400 AN: 152294 Hom.: 3 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74488

Gnomad4 AFR AF: 0.00816

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000584 Hom.: 0

Bravo AF: 0.00297

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000832 AC: 101

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	PKD2: BS1, BS2 -

Polycystic kidney disease 2 Uncertain:1 Benign:1

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. -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 21, 2022	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 11, 2016	- -

Polycystic kidney disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD2 p.Ser804Asn variant was identified in 1 of 404 proband chromosomes (frequency: 0.0025) from individuals or families with Autosomal Dominant PKD (Rossetti 2007). The variant was also identified in dbSNP (ID: rs145343957) as “With other allele”, in ClinVar (as benign by EGL Genetic Diagnostics and Invitae, and as uncertain significance by ARUP Laboratories), LOVD 3.0 (1x as "indeterminate"), and ADPKD Mutation Database. The variant was not identified in PKD1-LOVD. The variant was identified in control databases in 277 of 276842 chromosomes (1 homozygous) at a frequency of 0.001001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 179 of 24034 chromosomes (freq: 0.007), Other in 17 of 6460 chromosomes (freq: 0.003), Latino in 65 of 34394 chromosomes (freq: 0.002), European (Non-Finnish) in 16 of 126422 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The mutation is located within the consensus kinase recognition sequence; a functional study showed the p.Ser804Asn variant abolished Ser801 phosphorylation, indicating its likely physiological significance, and this study therefore classified the variant as pathogenic (Streets 2010). The p.Ser804 residue is 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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 kidney disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.73	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.082	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.60
MVP		0.69
MPC		0.59
ClinPred		0.025	T
GERP RS		5.7
Varity_R		0.18
gMVP		0.36

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: rs145343957; hg19: chr4-88989102;