16-2103467-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_001009944.3(PKD1):​c.8590G>A​(p.Glu2864Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000581 in 1,600,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.52
Variant links:
Genes affected
PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1642479).
BS2
High AC in GnomAd4 at 15 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKD1NM_001009944.3 linkc.8590G>A p.Glu2864Lys missense_variant Exon 23 of 46 ENST00000262304.9 NP_001009944.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKD1ENST00000262304.9 linkc.8590G>A p.Glu2864Lys missense_variant Exon 23 of 46 1 NM_001009944.3 ENSP00000262304.4 P98161-1

Frequencies

GnomAD3 genomes
AF:
0.0000985
AC:
15
AN:
152222
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000895
AC:
21
AN:
234554
Hom.:
0
AF XY:
0.000100
AC XY:
13
AN XY:
129776
show subpopulations
Gnomad AFR exome
AF:
0.000353
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000558
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000648
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000539
AC:
78
AN:
1448264
Hom.:
0
Cov.:
34
AF XY:
0.0000527
AC XY:
38
AN XY:
720978
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000766
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000163
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000477
Gnomad4 OTH exome
AF:
0.0000665
GnomAD4 genome
AF:
0.0000985
AC:
15
AN:
152340
Hom.:
0
Cov.:
31
AF XY:
0.000134
AC XY:
10
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000192
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000927
Hom.:
0
Bravo
AF:
0.0000756
ESP6500AA
AF:
0.000246
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000127
AC:
15
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 25, 2016
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Uncertain:1
Jan 25, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Dec 28, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.8590G>A (p.E2864K) alteration is located in exon 23 (coding exon 23) of the PKD1 gene. This alteration results from a G to A substitution at nucleotide position 8590, causing the glutamic acid (E) at amino acid position 2864 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PKD1-related disorder Uncertain:1
Oct 13, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PKD1 c.8590G>A variant is predicted to result in the amino acid substitution p.Glu2864Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.031% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2153468-C-T), which may be too common to be a primary cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
15
DANN
Benign
0.95
DEOGEN2
Benign
0.17
T;.
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.65
FATHMM_MKL
Benign
0.28
N
LIST_S2
Uncertain
0.91
D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.16
T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Uncertain
2.3
M;M
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-0.62
N;N
REVEL
Benign
0.15
Sift
Benign
0.78
T;T
Sift4G
Benign
0.54
T;T
Polyphen
0.89
P;D
Vest4
0.27
MVP
0.78
ClinPred
0.023
T
GERP RS
1.6
Varity_R
0.022
gMVP
0.48

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

LitVar

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

Other links and lift over

dbSNP: rs374629549; hg19: chr16-2153468; API