4-88007742-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000297.4(PKD2):c.9C>T(p.Asn3=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,207,562 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: PKD2 NM_000297.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.386

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 4-88007742-C-T is Benign according to our data. Variant chr4-88007742-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 903899.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BP7: Synonymous conserved (PhyloP=0.386 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00012 (127/1058142) while in subpopulation MID AF= 0.00198 (6/3030). AF 95% confidence interval is 0.000862. There are 1 homozygotes in gnomad4_exome. There are 62 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD2	NM_000297.4	c.9C>T	p.Asn3=	synonymous_variant	1/15	ENST00000237596.7
PKD2	XM_011532028.3	c.9C>T	p.Asn3=	synonymous_variant	1/14
PKD2	NR_156488.2	n.108C>T		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD2	ENST00000237596.7	c.9C>T	p.Asn3=	synonymous_variant	1/15	1	NM_000297.4	P1
	ENST00000662475.1	n.112+624G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000114 AC: 17 AN: 149420 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00175

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 12 AN: 57896 Hom.: 0 AF XY: 0.000202 AC XY: 7 AN XY: 34576

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000748

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000181

Gnomad OTH exome AF: 0.00119

GnomAD4 exome AF: 0.000120 AC: 127 AN: 1058142 Hom.: 1 Cov.: 28 AF XY: 0.000120 AC XY: 62 AN XY: 515084

Gnomad4 AFR exome AF: 0.0000485

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000557

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000716

Gnomad4 FIN exome AF: 0.0000601

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.000257

GnomAD4 genome AF: 0.000114 AC: 17 AN: 149420 Hom.: 0 Cov.: 32 AF XY: 0.0000960 AC XY: 7 AN XY: 72884

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00175

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000164

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000102

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD2 p.Asn3Asn variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, ADPKD Mutation Database or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs773343245) and in control databases in 14 of 85778 chromosomes at a frequency of 0.000163 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 2566 chromosomes (freq: 0.000779), Ashkenazi Jewish in 4 of 5596 chromosomes (freq: 0.000715), European (non-Finnish) in 6 of 36322 chromosomes (freq: 0.000165) and South Asian in 2 of 14048 chromosomes (freq: 0.000142), while the variant was not observed in the African, Latino, East Asian, and European (Finnish) populations. The p.Asn3Asn variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. Two of four in silico or computational prediction software programs (SpliceSiteFinder and MaxEntScan) predict the creation of a new 5' splice site, however this is not very predictive of pathogenecity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Polycystic kidney disease 2 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autosomal dominant polycystic kidney disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 22, 2023

- -

PKD2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	12
Dann	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs773343245; hg19: chr4-88928894;