rs3087632

Variant names:

• chr16-2090453-T-C
• rs3087632
• NM_001009944.3:c.12276A>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2090453-T-C
• chr16-2090453-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.12276A>G​(p.Ala4092Ala) 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 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/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.56
• Publications: 25 publications found

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]

MIR1225 (HGNC:33931): (microRNA 1225) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -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/Likely_benign. ClinVar VariationId is 256917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.12276A>G	p.Ala4092Ala	synonymous_variant	Exon 45 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.12276A>G	p.Ala4092Ala	synonymous_variant	Exon 45 of 46	1	NM_001009944.3	ENSP00000262304.4
PKD1	ENST00000423118.5	c.12273A>G	p.Ala4091Ala	synonymous_variant	Exon 45 of 46	1		ENSP00000399501.1
PKD1	ENST00000472577.1	n.304A>G		non_coding_transcript_exon_variant	Exon 2 of 3	2
MIR1225	ENST00000408729.1	n.-169A>G		upstream_gene_variant		6

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

GnomAD2 exomes AF: 0.186 AC: 45371 AN: 243712 AF XY: 0.178

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 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

African (AFR) AF: 0.648 AC: 21674 AN: 33456

American (AMR) AF: 0.135 AC: 6045 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 6804 AN: 26120

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39692

South Asian (SAS) AF: 0.0998 AC: 8609 AN: 86226

European-Finnish (FIN) AF: 0.222 AC: 11501 AN: 51916

Middle Eastern (MID) AF: 0.262 AC: 1508 AN: 5764

European-Non Finnish (NFE) AF: 0.180 AC: 199823 AN: 1111610

Other (OTH) AF: 0.202 AC: 12173 AN: 60342

GnomAD4 genome AF: 0.306 AC: 46499 AN: 152146 Hom.: 10535 Cov.: 35 AF XY: 0.301 AC XY: 22405 AN XY: 74382

African (AFR) AF: 0.638 AC: 26476 AN: 41500

American (AMR) AF: 0.211 AC: 3221 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 889 AN: 3468

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5168

South Asian (SAS) AF: 0.0968 AC: 468 AN: 4834

European-Finnish (FIN) AF: 0.231 AC: 2448 AN: 10604

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12254 AN: 67960

Other (OTH) AF: 0.269 AC: 566 AN: 2108

Alfa AF: 0.187 Hom.: 1173

Bravo AF: 0.318

Asia WGS AF: 0.0850 AC: 298 AN: 3478

EpiCase AF: 0.194

EpiControl AF: 0.194

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:2

Jul 07, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Inborn genetic diseases Benign:1

Jan 21, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 01, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.38
DANN	Benign	0.55
PhyloP100		-2.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3087632; hg19: chr16-2140454;