4-88019442-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000297.4(PKD2):c.596-16C>T variant causes a 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 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.918

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant polycystic kidney disease
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
polycystic kidney disease 2
Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

PKD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 255796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
PKD2	NM_000297.4 link	c.596-16C>T	intron_variant	Intron 1 of 14	ENST00000237596.7	NP_000288.1
PKD2	NM_001440544.1 link	c.596-16C>T	intron_variant	Intron 1 of 13		NP_001427473.1
PKD2	NR_156488.2 link	n.695-16C>T	intron_variant	Intron 1 of 13
PKD2	XM_011532029.2 link	c.-197C>T	upstream_gene_variant			XP_011530331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 link	c.596-16C>T		intron_variant	Intron 1 of 14	1	NM_000297.4	ENSP00000237596.2
PKD2	ENST00000506727.1 link	n.98-16C>T		intron_variant	Intron 1 of 3	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

GnomAD2 exomes

AF:

0.0228

AC:

5548

AN:

243680

AF XY:

0.0234

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 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

African (AFR)

AF:

0.00380

AC:

AN:

25494

American (AMR)

AF:

0.0308

AC:

1353

AN:

43980

Ashkenazi Jewish (ASJ)

AF:

0.00773

AC:

183

AN:

23676

East Asian (EAS)

AF:

0.000293

AC:

AN:

37494

South Asian (SAS)

AF:

0.0289

AC:

2231

AN:

77316

European-Finnish (FIN)

AF:

0.0301

AC:

1594

AN:

53020

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

4952

European-Non Finnish (NFE)

AF:

0.0256

AC:

19310

AN:

754764

Other (OTH)

AF:

0.0201

AC:

952

AN:

47356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1137

2274

3411

4548

5685

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

570

1140

1710

2280

2850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0195

AC:

2963

AN:

151796

Hom.:

Cov.:

AF XY:

0.0200

AC XY:

1480

AN XY:

74160

show subpopulations

African (AFR)

AF:

0.00435

AC:

180

AN:

41398

American (AMR)

AF:

0.0242

AC:

370

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.000970

AC:

AN:

5156

South Asian (SAS)

AF:

0.0307

AC:

147

AN:

4786

European-Finnish (FIN)

AF:

0.0332

AC:

347

AN:

10462

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0270

AC:

1837

AN:

67952

Other (OTH)

AF:

0.0147

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

143

287

430

574

717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0237

Hom.:

Bravo

AF:

0.0178

Asia WGS

AF:

0.0140

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease 2

Benign:1

Mar 20, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.1

(source)

DANN

Benign

0.59

PhyloP100

-0.92

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over