chr16-2090453-T-C

Position:

chr16-2090453-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001009944.3(PKD1):c.12276A>G(p.Ala4092=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,611,916 control chromosomes in the GnomAD database, including 40,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A4092A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.31 ( 10535 hom., cov: 35)

Exomes 𝑓: 0.18 ( 29799 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.56

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 16-2090453-T-C is Benign according to our data. Variant chr16-2090453-T-C is described in ClinVar as [Benign]. Clinvar id is 256917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2090453-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.12276A>G	p.Ala4092=	synonymous_variant	45/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.12276A>G	p.Ala4092=	synonymous_variant	45/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.12273A>G	p.Ala4091=	synonymous_variant	45/46	1		ENSP00000399501	A2	P98161-3
PKD1	ENST00000472577.1 linkuse as main transcript	n.304A>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.305

AC:

46413

AN:

152028

Hom.:

10504

Cov.:

show subpopulations

Gnomad AFR

AF:

0.638

Gnomad AMI

AF:

0.0978

Gnomad AMR

AF:

0.211

Gnomad ASJ

AF:

0.256

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0971

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.271

GnomAD3 exomes

AF:

0.186

AC:

45371

AN:

243712

Hom.:

6439

AF XY:

0.178

AC XY:

23714

AN XY:

133016

show subpopulations

Gnomad AFR exome

AF:

0.640

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.255

Gnomad EAS exome

AF:

0.000219

Gnomad SAS exome

AF:

0.0966

Gnomad FIN exome

AF:

0.222

Gnomad NFE exome

AF:

0.183

Gnomad OTH exome

AF:

0.195

GnomAD4 exome

AF:

0.184

AC:

268150

AN:

1459770

Hom.:

29799

Cov.:

AF XY:

0.180

AC XY:

130610

AN XY:

726156

show subpopulations

Gnomad4 AFR exome

AF:

0.648

Gnomad4 AMR exome

AF:

0.135

Gnomad4 ASJ exome

AF:

0.260

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.0998

Gnomad4 FIN exome

AF:

0.222

Gnomad4 NFE exome

AF:

0.180

Gnomad4 OTH exome

AF:

0.202

GnomAD4 genome

AF:

0.306

AC:

46499

AN:

152146

Hom.:

10535

Cov.:

AF XY:

0.301

AC XY:

22405

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.638

Gnomad4 AMR

AF:

0.211

Gnomad4 ASJ

AF:

0.256

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.0968

Gnomad4 FIN

AF:

0.231

Gnomad4 NFE

AF:

0.180

Gnomad4 OTH

AF:

0.269

Alfa

AF:

0.180

Hom.:

1026

Bravo

AF:

0.318

Asia WGS

AF:

0.0850

AC:

298

AN:

3478

EpiCase

AF:

0.194

EpiControl

AF:

0.194

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2019	This variant is associated with the following publications: (PMID: 32957937) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The 12276A>G, p.Ala4092Ala variant was identified in 19.6% of 22546 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

Autosomal dominant polycystic kidney disease

Benign:1

Benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.38

DANN

Benign

0.55

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

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