16-2090009-A-G

Variant names:

• chr16-2090009-A-G
• rs7203729
• NM_001009944.3:c.12630T>C

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.12630T>C​(p.Pro4210Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,608,974 control chromosomes in the GnomAD database, including 41,941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (10754 hom., cov: 34)
  • Exomes 𝑓: 0.19 (31187 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -7.93
• Publications: 21 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=-1.01).
• BP6: Variant 16-2090009-A-G is Benign according to our data. Variant chr16-2090009-A-G is described in ClinVar as Benign. ClinVar VariationId is 256921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.93 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.636 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.12630T>C	p.Pro4210Pro	synonymous	Exon 46 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.12627T>C	p.Pro4209Pro	synonymous	Exon 46 of 46	NP_000287.4
	MIR1225	NR_030646.1		n.*186T>C		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.12630T>C	p.Pro4210Pro	synonymous	Exon 46 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.12627T>C	p.Pro4209Pro	synonymous	Exon 46 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000472577.1	TSL:2	n.658T>C		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46954 AN: 152060 Hom.: 10724 Cov.: 34

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0935

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.271

GnomAD2 exomes AF: 0.188 AC: 44766 AN: 237720 AF XY: 0.180

Gnomad AFR exome AF: 0.648

Gnomad AMR exome AF: 0.127

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.000282

Gnomad FIN exome AF: 0.224

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.189 AC: 275325 AN: 1456796 Hom.: 31187 Cov.: 34 AF XY: 0.185 AC XY: 133823 AN XY: 724520

African (AFR) AF: 0.652 AC: 21811 AN: 33446

American (AMR) AF: 0.136 AC: 5996 AN: 43984

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 6648 AN: 25910

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39594

South Asian (SAS) AF: 0.0958 AC: 8228 AN: 85928

European-Finnish (FIN) AF: 0.223 AC: 11531 AN: 51612

Middle Eastern (MID) AF: 0.263 AC: 1513 AN: 5760

European-Non Finnish (NFE) AF: 0.187 AC: 207116 AN: 1110418

Other (OTH) AF: 0.207 AC: 12469 AN: 60144

GnomAD4 genome AF: 0.309 AC: 47039 AN: 152178 Hom.: 10754 Cov.: 34 AF XY: 0.304 AC XY: 22625 AN XY: 74406

African (AFR) AF: 0.643 AC: 26678 AN: 41498

American (AMR) AF: 0.210 AC: 3217 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 867 AN: 3472

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5176

South Asian (SAS) AF: 0.0932 AC: 450 AN: 4828

European-Finnish (FIN) AF: 0.233 AC: 2470 AN: 10604

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

European-Non Finnish (NFE) AF: 0.186 AC: 12612 AN: 67986

Other (OTH) AF: 0.268 AC: 567 AN: 2112

Alfa AF: 0.190 Hom.: 1222

Bravo AF: 0.322

Asia WGS AF: 0.0860 AC: 300 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.13
DANN	Benign	0.39
PhyloP100		-7.9
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7203729; hg19: chr16-2140010;