rs1311664031

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_001009944.3(PKD1):​c.2200G>A​(p.Gly734Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 1,237,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.974
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 -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.052439272).
BS2
High AC in GnomAdExome4 at 23 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/exons MANE Protein UniProt
PKD1NM_001009944.3 linkuse as main transcriptc.2200G>A p.Gly734Ser missense_variant 11/46 ENST00000262304.9 NP_001009944.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PKD1ENST00000262304.9 linkuse as main transcriptc.2200G>A p.Gly734Ser missense_variant 11/461 NM_001009944.3 ENSP00000262304 P5P98161-1
PKD1ENST00000423118.5 linkuse as main transcriptc.2200G>A p.Gly734Ser missense_variant 11/461 ENSP00000399501 A2P98161-3
PKD1ENST00000488185.2 linkuse as main transcriptc.472+2666G>A intron_variant 5 ENSP00000456672
PKD1ENST00000568591.5 linkuse as main transcriptc.*528G>A 3_prime_UTR_variant, NMD_transcript_variant 7/122 ENSP00000457162

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152034
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000497
AC:
6
AN:
120686
Hom.:
0
AF XY:
0.0000154
AC XY:
1
AN XY:
64726
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000127
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000534
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000427
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
23
AN:
1085756
Hom.:
0
Cov.:
16
AF XY:
0.0000183
AC XY:
10
AN XY:
546810
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000170
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000585
Gnomad4 SAS exome
AF:
0.0000275
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000160
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152034
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000302

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health SystemAug 25, 2016- -
Polycystic kidney disease, adult type Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 19, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.50
T
BayesDel_noAF
Benign
-0.75
CADD
Benign
0.038
DANN
Benign
0.62
DEOGEN2
Benign
0.12
T;.
Eigen
Benign
-1.9
Eigen_PC
Benign
-1.9
FATHMM_MKL
Benign
0.0042
N
LIST_S2
Benign
0.38
T;T
M_CAP
Benign
0.053
D
MetaRNN
Benign
0.052
T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.35
N;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
0.75
N;N
REVEL
Benign
0.016
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.024
B;B
Vest4
0.026
MutPred
0.23
Gain of glycosylation at G734 (P = 0.0018);Gain of glycosylation at G734 (P = 0.0018);
MVP
0.35
ClinPred
0.032
T
GERP RS
-8.6
Varity_R
0.027
gMVP
0.20

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: rs1311664031; hg19: chr16-2164824; API