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rs547817931

chr16-2111261-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_001009944.3(PKD1):c.3906C>T(p.Ala1302=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,610,064 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

2

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -3.18
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 Benign. Variant got -10 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-2111261-G-A is Benign according to our data. Variant chr16-2111261-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433959.Status of the report is no_assertion_criteria_provided, 0 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-3.18 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PKD1NM_001009944.3 linkuse as main transcriptc.3906C>T p.Ala1302= synonymous_variant 15/46 ENST00000262304.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PKD1ENST00000262304.9 linkuse as main transcriptc.3906C>T p.Ala1302= synonymous_variant 15/461 NM_001009944.3 P5P98161-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000526
AC:
8
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00103
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000278
AC:
67
AN:
240972
Hom.:
2
AF XY:
0.000356
AC XY:
47
AN XY:
132198
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000113
Gnomad SAS exome
AF:
0.00193
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000557
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000134
AC:
196
AN:
1457730
Hom.:
2
Cov.:
36
AF XY:
0.000214
AC XY:
155
AN XY:
725288
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00204
Gnomad4 FIN exome
AF:
0.0000197
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.0000996
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000525
AC:
8
AN:
152334
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00103
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000677
Hom.:
0
Bravo
AF:
0.00000756
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

Polycystic kidney disease Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The PKD1 p.Ala1302Ala variant was not identified in the literature nor was it identified in the - Clinvitae, ClinVar, GeneInsight COGR, MutDB, ADPKD Mutation Database, PKD1-LOVD, and PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs547817931) as “N/A”, in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), the Exome Aggregation Consortium database (August 8, 2016) in 39 (1 homozygous) of 111838 chromosomes (freq. 0.0003) in the following populations: South Asian in 36 of 16250 chromosomes (freq. 0.002), European in 2 of 61142 chromosomes (freq.0.00003), and European in 1 of 8226 chromosomes (freq. 0.0001), increasing the likelihood this could be a low frequency benign variant. The p.Ala1302Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, the variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In addition, this variant was identified in one individual by our laboratory as co-occurring with a pathogenic variant in PKD1 (c.12010CT, p.Gln4004X), increasing the likelihood this variant does not have clinical significance. 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. 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
0.26
Dann
Benign
0.72
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs547817931; hg19: chr16-2161262; API