4-88075950-C-T

Variant names:

• chr4-88075950-C-T
• rs2728121
• NM_000297.4:c.*256C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000297.4(PKD2):​c.*256C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 460,598 control chromosomes in the GnomAD database, including 6,111 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1749 hom., cov: 32)
  • Exomes 𝑓: 0.15 (4362 hom.)
• Consequence: PKD2 NM_000297.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0690
• Publications: 23 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4	c.*256C>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000237596.7	NP_000288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.*256C>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_000297.4	ENSP00000237596.2

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20504 AN: 151886 Hom.: 1746 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.0903

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.150 AC: 46170 AN: 308594 Hom.: 4362 Cov.: 0 AF XY: 0.150 AC XY: 24731 AN XY: 164514

African (AFR) AF: 0.133 AC: 1232 AN: 9234

American (AMR) AF: 0.221 AC: 2975 AN: 13476

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 1251 AN: 9446

East Asian (EAS) AF: 0.438 AC: 8603 AN: 19646

South Asian (SAS) AF: 0.152 AC: 5719 AN: 37666

European-Finnish (FIN) AF: 0.139 AC: 2093 AN: 15094

Middle Eastern (MID) AF: 0.113 AC: 144 AN: 1278

European-Non Finnish (NFE) AF: 0.116 AC: 21431 AN: 185074

Other (OTH) AF: 0.154 AC: 2722 AN: 17680

GnomAD4 genome AF: 0.135 AC: 20547 AN: 152004 Hom.: 1749 Cov.: 32 AF XY: 0.139 AC XY: 10354 AN XY: 74282

African (AFR) AF: 0.127 AC: 5267 AN: 41460

American (AMR) AF: 0.165 AC: 2512 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 470 AN: 3466

East Asian (EAS) AF: 0.464 AC: 2396 AN: 5160

South Asian (SAS) AF: 0.142 AC: 687 AN: 4824

European-Finnish (FIN) AF: 0.130 AC: 1365 AN: 10538

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7479 AN: 67986

Other (OTH) AF: 0.124 AC: 262 AN: 2108

Alfa AF: 0.120 Hom.: 4157

Bravo AF: 0.141

Asia WGS AF: 0.327 AC: 1136 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant polycystic kidney disease Benign:1

Feb 19, 2016

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.5
DANN	Benign	0.52
PhyloP100		0.069
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2728121; hg19: chr4-88997102;