4-88007652-G-C

Position:

• chr4-88007652-G-C

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.-82G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 941,466 control chromosomes in the GnomAD database, including 267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (33 hom., cov: 33)
  • Exomes 𝑓: 0.022 (234 hom.)
• Consequence: PKD2 NM_000297.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.389

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]

ENSG00000286618 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 4-88007652-G-C is Benign according to our data. Variant chr4-88007652-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 350007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88007652-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0168 (2538/150916) while in subpopulation SAS AF= 0.047 (227/4832). AF 95% confidence interval is 0.042. There are 33 homozygotes in gnomad4. There are 1373 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2538 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4	c.-82G>C		5_prime_UTR_variant	1/15	ENST00000237596.7	NP_000288.1
PKD2	XM_011532028.3	c.-82G>C		5_prime_UTR_variant	1/14		XP_011530330.1
PKD2	NR_156488.2	n.18G>C		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596	c.-82G>C		5_prime_UTR_variant	1/15	1	NM_000297.4	ENSP00000237596.2
ENSG00000286618	ENST00000662475.1	n.112+714C>G		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2534 AN: 150806 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00397

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.0373

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0469

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0174

GnomAD4 exome AF: 0.0220 AC: 17375 AN: 790550 Hom.: 234 Cov.: 11 AF XY: 0.0221 AC XY: 8260 AN XY: 374034

Gnomad4 AFR exome AF: 0.00214

Gnomad4 AMR exome AF: 0.0120

Gnomad4 ASJ exome AF: 0.0328

Gnomad4 EAS exome AF: 0.000125

Gnomad4 SAS exome AF: 0.0467

Gnomad4 FIN exome AF: 0.0297

Gnomad4 NFE exome AF: 0.0218

Gnomad4 OTH exome AF: 0.0233

GnomAD4 genome AF: 0.0168 AC: 2538 AN: 150916 Hom.: 33 Cov.: 33 AF XY: 0.0186 AC XY: 1373 AN XY: 73766

Gnomad4 AFR AF: 0.00406

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.0373

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.0470

Gnomad4 FIN AF: 0.0412

Gnomad4 NFE AF: 0.0196

Gnomad4 OTH AF: 0.0172

Alfa AF: 0.00397 Hom.: 2

Bravo AF: 0.0139

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.80

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs529779778; hg19: chr4-88928804;