Genetic Variant PKD2:p.Arg28Leu (chr4-88007816-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000297.4(PKD2):c.83G>T(p.Arg28Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000976 in 1,025,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R28W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.8e-7 ( 0 hom. )

Consequence

PKD2
NM_000297.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.853

Publications

0 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:

ENSG00000286618 (HGNC:):

ENSG00000286618 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12967816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PKD2	NM_000297.4 link	c.83G>T	p.Arg28Leu	missense_variant	Exon 1 of 15	ENST00000237596.7	NP_000288.1
PKD2	NM_001440544.1 link	c.83G>T	p.Arg28Leu	missense_variant	Exon 1 of 14		NP_001427473.1
PKD2	NR_156488.2 link	n.182G>T		non_coding_transcript_exon_variant	Exon 1 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 link	c.83G>T	p.Arg28Leu	missense_variant	Exon 1 of 15	1	NM_000297.4	ENSP00000237596.2
ENSG00000286618	ENST00000662475.1 link	n.112+550C>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.76e-7

AC:

AN:

1025042

Hom.:

Cov.:

AF XY:

0.00000206

AC XY:

AN XY:

485810

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20452

American (AMR)

AF:

0.00

AC:

AN:

6444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11478

East Asian (EAS)

AF:

0.00

AC:

AN:

20662

South Asian (SAS)

AF:

0.00

AC:

AN:

19798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2606

European-Non Finnish (NFE)

AF:

0.00000113

AC:

AN:

886184

Other (OTH)

AF:

0.00

AC:

AN:

39056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.60

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

PhyloP100

0.85

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.55

REVEL

Benign

0.040

Sift

Uncertain

0.010

Sift4G

Benign

0.14

Polyphen

0.0080

Vest4

0.15

MutPred

0.38

Loss of methylation at R28 (P = 0.031);

MVP

0.20

MPC

0.68

ClinPred

0.49

GERP RS

0.55

PromoterAI

0.17

Neutral

(source)

Varity_R

0.12

gMVP

0.28

Mutation Taster

=86/14

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over