rs3087632

chr16-2090453-T-Cchr16-2090453-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.56

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]

ACMG classification

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	UniProt
PKD1	NM_001009944.3	c.12276A>G	p.Ala4092=	synonymous_variant	45/46	ENST00000262304.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46413 AN: 152028 Hom.: 10504 Cov.: 35

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

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.: 35 AF XY: 0.180 AC XY: 130610 AN XY: 726156

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.: 35 AF XY: 0.301 AC XY: 22405 AN XY: 74382

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:2

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

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2019

This variant is associated with the following publications: (PMID: 32957937) -

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

Other links and lift over

dbSNP: rs3087632; hg19: chr16-2140454;