rs62310565

Positions:

• chr4-88019442-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.918

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 -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	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4	c.596-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000237596.7	NP_000288.1
PKD2	XM_011532028.3	c.596-16C>T		splice_polypyrimidine_tract_variant, intron_variant			XP_011530330.1
PKD2	NR_156488.2	n.695-16C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.596-16C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000297.4	ENSP00000237596	P1
PKD2	ENST00000506727.1	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.: 38 Cov.: 32

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.: 85 AF XY: 0.0234 AC XY: 3087 AN XY: 132158

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.: 15 AF XY: 0.0244 AC XY: 13396 AN XY: 549788

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.: 38 Cov.: 32 AF XY: 0.0200 AC XY: 1480 AN XY: 74160

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.: 9

Bravo AF: 0.0178

Asia WGS AF: 0.0140 AC: 49 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Other links and lift over

dbSNP: rs62310565; hg19: chr4-88940594;