rs62310565

Positions:

chr4-88019442-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000297.4(PKD2):c.596-16C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,219,848 control chromosomes in the GnomAD database, including 448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 38 hom., cov: 32)

Exomes 𝑓: 0.024 ( 410 hom. )

Consequence

PKD2
NM_000297.4 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.918

Variant links:

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]

PKD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 4-88019442-C-T is Benign according to our data. Variant chr4-88019442-C-T is described in ClinVar as [Benign]. Clinvar id is 255796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88019442-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0195 (2963/151796) while in subpopulation SAS AF= 0.0307 (147/4786). AF 95% confidence interval is 0.0267. There are 38 homozygotes in gnomad4. There are 1480 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2963 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
PKD2	NM_000297.4 linkuse as main transcript	c.596-16C>T	splice_polypyrimidine_tract_variant, intron_variant	ENST00000237596.7
PKD2	XM_011532028.3 linkuse as main transcript	c.596-16C>T	splice_polypyrimidine_tract_variant, intron_variant
PKD2	NR_156488.2 linkuse as main transcript	n.695-16C>T	splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD2	ENST00000237596.7 linkuse as main transcript	c.596-16C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000297.4	P1	Q13563-1
PKD2	ENST00000506727.1 linkuse as main transcript	n.98-16C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0195

AC:

2963

AN:

151682

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00436

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.0243

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000967

Gnomad SAS

AF:

0.0305

Gnomad FIN

AF:

0.0332

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0270

Gnomad OTH

AF:

0.0149

GnomAD3 exomes

AF:

0.0228

AC:

5548

AN:

243680

Hom.:

AF XY:

0.0234

AC XY:

3087

AN XY:

132158

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.0320

Gnomad ASJ exome

AF:

0.00689

Gnomad EAS exome

AF:

0.000392

Gnomad SAS exome

AF:

0.0263

Gnomad FIN exome

AF:

0.0314

Gnomad NFE exome

AF:

0.0254

Gnomad OTH exome

AF:

0.0182

GnomAD4 exome

AF:

0.0242

AC:

25805

AN:

1068052

Hom.:

410

Cov.:

AF XY:

0.0244

AC XY:

13396

AN XY:

549788

show subpopulations

Gnomad4 AFR exome

AF:

0.00380

Gnomad4 AMR exome

AF:

0.0308

Gnomad4 ASJ exome

AF:

0.00773

Gnomad4 EAS exome

AF:

0.000293

Gnomad4 SAS exome

AF:

0.0289

Gnomad4 FIN exome

AF:

0.0301

Gnomad4 NFE exome

AF:

0.0256

Gnomad4 OTH exome

AF:

0.0201

GnomAD4 genome

AF:

0.0195

AC:

2963

AN:

151796

Hom.:

Cov.:

AF XY:

0.0200

AC XY:

1480

AN XY:

74160

show subpopulations

Gnomad4 AFR

AF:

0.00435

Gnomad4 AMR

AF:

0.0242

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.000970

Gnomad4 SAS

AF:

0.0307

Gnomad4 FIN

AF:

0.0332

Gnomad4 NFE

AF:

0.0270

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0237

Hom.:

Bravo

AF:

0.0178

Asia WGS

AF:

0.0140

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD2 c.596-16C>T variant was identified in 25 of 510 proband chromosomes (frequency: 0.049) from individuals or families with ADPKD (Rossetti 2012, Tan 2009). The variant was also identified in dbSNP (ID: rs62310565) and ADPKD Mutation Database (classified as likely neutral). This variant was identified in the 1000 Genomes Project in 57 of 5000 chromosomes (frequency: 0.0114), NHLBI GO Exome Sequencing Project in 167 of 8598 European American and in 11 of 4404 African American alleles; Exome Aggregation Consortium database (March 14, 2016) in 2582 (38 homozygous) of 93876 chromosomes (freq. 0.0275) in the following populations: European in 1502 of 51240 chromosomes (freq. 0.029), South Asian in 430 of 13452 chromosomes (freq. 0.032), Latino in 403 of 10172 chromosomes (freq. 0.04), Finnish in 192 of 5714 chromosomes (freq. 0.034), African in 30 of 7354 chromosomes (freq. 0.004), East Asian in 4 of 5172 chromosomes (freq. 0.001), Other in 21 of 772 chromosomes (freq. 0.027), 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 c.596-16C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Polycystic kidney disease 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.1

DANN

Benign

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over