NM_001009944.3:c.8087T>C

Variant summary

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

The NM_001009944.3(PKD1):ā€‹c.8087T>Cā€‹(p.Leu2696Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,593,812 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 (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2696R) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.00027 ( 0 hom., cov: 20)
Exomes š‘“: 0.00024 ( 0 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.659
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=0.089800954).
BS2
High AC in GnomAd4 at 39 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.8087T>C p.Leu2696Pro missense_variant Exon 22 of 46 ENST00000262304.9 NP_001009944.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKD1ENST00000262304.9 linkc.8087T>C p.Leu2696Pro missense_variant Exon 22 of 46 1 NM_001009944.3 ENSP00000262304.4 P98161-1

Frequencies

GnomAD3 genomes
AF:
0.000268
AC:
39
AN:
145590
Hom.:
0
Cov.:
20
show subpopulations
Gnomad AFR
AF:
0.0000512
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000136
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000532
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000158
AC:
27
AN:
170576
Hom.:
0
AF XY:
0.000184
AC XY:
17
AN XY:
92332
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000386
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000242
AC:
350
AN:
1448110
Hom.:
0
Cov.:
30
AF XY:
0.000230
AC XY:
166
AN XY:
720204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000307
Gnomad4 OTH exome
AF:
0.000167
GnomAD4 genome
AF:
0.000268
AC:
39
AN:
145702
Hom.:
0
Cov.:
20
AF XY:
0.000254
AC XY:
18
AN XY:
70986
show subpopulations
Gnomad4 AFR
AF:
0.0000510
Gnomad4 AMR
AF:
0.000136
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000532
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000364
Hom.:
0
ExAC
AF:
0.0000175
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type Uncertain:1
Mar 22, 2019
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PKD1 c.8087T>C; p.Leu2696Pro variant (rs201238819) is reported in the literature in an individual affected with autosomal dominant polycystic kidney disease, but it was not considered to be disease-causing (Rossetti 2007). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (33/84186 alleles) in the Genome Aggregation Database. The leucine at codon 2696 is not conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Leu2696Pro variant is uncertain at this time. References: Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 Jul;18(7):2143-60. -

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

The PKD1 p.Leu2696Pro variant was identified in 1 of 404 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD however this variant was not considered disease causing because of the highly nonconservative nature of this site in orthologs (Rossetti 2007). This variant was also identified in the ADPKD Mutation Database (classified as likely neutral by Athena Diagnostics). The variant was not identified in LOVD 3.0 or PKD1-LOVD databases. The variant was identified in control databases in 25 of 164086 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 25 of 66866 chromosomes (freq: 0.0004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. An alternative substitution at this position resulting in a different amino acid change (c.8087T>G, p.Leu2696Arg) was identified by our laboratory and classified as benign (this is the substitution recorded for this position in dbSNP (rs201238819) and ClinVar). The p.Leu2696 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
8.7
DANN
Benign
0.85
DEOGEN2
Benign
0.19
T;.
Eigen
Benign
-0.98
Eigen_PC
Benign
-0.99
FATHMM_MKL
Benign
0.37
N
LIST_S2
Benign
0.19
T;T
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.090
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N
PrimateAI
Benign
0.43
T
PROVEAN
Benign
0.49
N;N
REVEL
Benign
0.14
Sift
Benign
0.18
T;T
Sift4G
Benign
0.30
T;T
Polyphen
0.23
B;P
Vest4
0.19
MutPred
0.48
Loss of stability (P = 0.0545);Loss of stability (P = 0.0545);
MVP
0.68
ClinPred
0.039
T
GERP RS
-1.7
Varity_R
0.076
gMVP
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs201238819; hg19: chr16-2154573; API