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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.12276A>G	p.Ala4092Ala	synonymous	Exon 45 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.12273A>G	p.Ala4091Ala	synonymous	Exon 45 of 46	NP_000287.4
	MIR1225	NR_030646.1		n.-169A>G		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.12276A>G	p.Ala4092Ala	synonymous	Exon 45 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.12273A>G	p.Ala4091Ala	synonymous	Exon 45 of 46	ENSP00000399501.1
	PKD1	ENST00000472577.1	TSL:2	n.304A>G		non_coding_transcript_exon	Exon 2 of 3

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

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;