chr16-2114928-G-A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001009944.3(PKD1):​c.2098-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,529,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

PKD1
NM_001009944.3 splice_region, intron

Scores

2
Splicing: ADA: 0.0002725
2

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.443

Publications

0 publications found
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]
PKD1 Gene-Disease associations (from GenCC):
  • autosomal dominant polycystic kidney disease
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • polycystic kidney disease 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • autosomal recessive polycystic kidney disease
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • Caroli disease
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 16-2114928-G-A is Benign according to our data. Variant chr16-2114928-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433950.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKD1NM_001009944.3 linkc.2098-3C>T splice_region_variant, intron_variant Intron 10 of 45 ENST00000262304.9 NP_001009944.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKD1ENST00000262304.9 linkc.2098-3C>T splice_region_variant, intron_variant Intron 10 of 45 1 NM_001009944.3 ENSP00000262304.4 P98161-1
PKD1ENST00000423118.5 linkc.2098-3C>T splice_region_variant, intron_variant Intron 10 of 45 1 ENSP00000399501.1 P98161-3
PKD1ENST00000488185.2 linkc.470+2561C>T intron_variant Intron 2 of 4 5 ENSP00000456672.1 H3BSE9
PKD1ENST00000568591.5 linkn.*426-3C>T splice_region_variant, intron_variant Intron 6 of 11 2 ENSP00000457162.1 H3BTG3

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152250
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000391
AC:
4
AN:
102202
AF XY:
0.0000188
show subpopulations
Gnomad AFR exome
AF:
0.000161
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000254
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000261
AC:
36
AN:
1377740
Hom.:
0
Cov.:
30
AF XY:
0.0000265
AC XY:
18
AN XY:
680526
show subpopulations
African (AFR)
AF:
0.0000317
AC:
1
AN:
31520
American (AMR)
AF:
0.00
AC:
0
AN:
36050
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25150
East Asian (EAS)
AF:
0.0000555
AC:
2
AN:
36046
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79134
European-Finnish (FIN)
AF:
0.0000295
AC:
1
AN:
33952
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4056
European-Non Finnish (NFE)
AF:
0.0000298
AC:
32
AN:
1074228
Other (OTH)
AF:
0.00
AC:
0
AN:
57604
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.438
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
AF:
0.0000328
AC:
5
AN:
152250
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74386
show subpopulations
African (AFR)
AF:
0.0000482
AC:
2
AN:
41470
American (AMR)
AF:
0.00
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000385
AC:
2
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Polycystic kidney disease Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

The PKD1 c.2098-3C>T variant was not identified in the literature nor was it identified in dbSNP, Clinvitae database, the ClinVar database, GeneInsight COGR database, ADPKD Mutation Database, PKD1-LOVD, PKD1-LOVD 3.0, 1000 Genomes Project, NHLBI GO Exome Sequencing Project (ESP), and the Exome Aggregation Consortium database (March 14, 2016). The c.2098-3C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site; however, HumanSpliceFinder, MaxEntScan and GeneSplicer predict the loss of a 5' cryptic donor splice site at this position and we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. In addition this variant was identified co-occurring with a pathogenic PKD1 variant (PKD1, EXON43, c.11798_11810del, p.Leu3933ArgfsX8) in a patient with a clinical diagnosis of ADPKD . This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
1.2
DANN
Benign
0.80
PhyloP100
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00027
dbscSNV1_RF
Benign
0.12
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs1295368570; hg19: chr16-2164929; API