4-88007742-C-T

Position:

chr4-88007742-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000297.4(PKD2):c.9C>T(p.Asn3Asn) 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.386

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 links:

ENSG00000286618 (HGNC:):

ENSG00000286618 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=1}.

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 GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4 link	c.9C>T	p.Asn3Asn	synonymous_variant	1/15	ENST00000237596.7	NP_000288.1	Q13563-1Q9UEU6
PKD2	XM_011532028.3 link	c.9C>T	p.Asn3Asn	synonymous_variant	1/14		XP_011530330.1
PKD2	NR_156488.2 link	n.108C>T		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 link	c.9C>T	p.Asn3Asn	synonymous_variant	1/15	1	NM_000297.4	ENSP00000237596.2		Q13563-1
ENSG00000286618	ENST00000662475.1 link	n.112+624G>A		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.000114

AC:

AN:

149420

Hom.:

Cov.:

show subpopulations

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:

AN:

57896

Hom.:

AF XY:

0.000202

AC XY:

AN XY:

34576

show subpopulations

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.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

515084

show subpopulations

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:

AN:

149420

Hom.:

Cov.:

AF XY:

0.0000960

AC XY:

AN XY:

72884

show subpopulations

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.:

Bravo

AF:

0.000102

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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. -

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. -

Autosomal dominant polycystic kidney disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

- -

PKD2-related disorder

Benign:1

Likely benign, no assertion criteria provided

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over