16-2091483-G-A

Position:

chr16-2091483-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_001009944.3(PKD1):c.11652C>T(p.Ser3884=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,378,046 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 Benign (★).

Frequency

Genomes: 𝑓 0.00045 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.0420

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 links:

PKD1-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

PKD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 16-2091483-G-A is Benign according to our data. Variant chr16-2091483-G-A is described in ClinVar as [Benign]. Clinvar id is 434004.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2091483-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.042 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000447 (67/149888) while in subpopulation EAS AF= 0.0123 (63/5128). AF 95% confidence interval is 0.00985. There are 1 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.11652C>T	p.Ser3884=	synonymous_variant	42/46	ENST00000262304.9	NP_001009944.3
PKD1-AS1	NR_135175.1 linkuse as main transcript	n.48G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.11652C>T	p.Ser3884=	synonymous_variant	42/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

149780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000665

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0122

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000612

AC:

AN:

39214

Hom.:

AF XY:

0.000507

AC XY:

AN XY:

23678

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0103

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000832

GnomAD4 exome

AF:

0.000103

AC:

127

AN:

1228158

Hom.:

Cov.:

AF XY:

0.0000895

AC XY:

AN XY:

603220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00390

Gnomad4 SAS exome

AF:

0.0000159

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000995

Gnomad4 OTH exome

AF:

0.000387

GnomAD4 genome

AF:

0.000447

AC:

AN:

149888

Hom.:

Cov.:

AF XY:

0.000492

AC XY:

AN XY:

73182

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000665

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0123

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000423

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 07, 2019

- -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ser3884= variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs377436997) as â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, and ADPKD Mutation Database (classified likely neutral). The variant was identified in control databases in 52 (2 homozygous) of 67022 chromosomes at a frequency of 0.0008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 1998 chromosomes (freq: 0.0005), East Asian in 51 (2 homozygous) of 3682 chromosomes (freq: 0.01) while not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The variant was also identified by our laboratory in 1 individual with polycystic kidneys. The p.Ser3884= 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, 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 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

-0.64

CADD

Benign

1.3

DANN

Benign

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over