rs79899502

Variant names:

• chr16-2090320-G-A
• rs79899502
• NM_001009944.3:c.12409C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.12409C>T​(p.Leu4137Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0713 in 1,611,706 control chromosomes in the GnomAD database, including 4,654 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (358 hom., cov: 34)
  • Exomes 𝑓: 0.073 (4296 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.19
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 16-2090320-G-A is Benign according to our data. Variant chr16-2090320-G-A is described in ClinVar as Benign. ClinVar VariationId is 256918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0739 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.12409C>T	p.Leu4137Leu	synonymous	Exon 45 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.12406C>T	p.Leu4136Leu	synonymous	Exon 45 of 46	NP_000287.4
	MIR1225	NR_030646.1		n.-36C>T		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.12409C>T	p.Leu4137Leu	synonymous	Exon 45 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.12406C>T	p.Leu4136Leu	synonymous	Exon 45 of 46	ENSP00000399501.1
	PKD1	ENST00000472577.1	TSL:2	n.437C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0566 AC: 8619 AN: 152152 Hom.: 358 Cov.: 34

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0591

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0756

Gnomad OTH AF: 0.0478

GnomAD2 exomes AF: 0.0656 AC: 16108 AN: 245388 AF XY: 0.0681

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.0272

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.000274

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.0796

Gnomad OTH exome AF: 0.0686

GnomAD4 exome AF: 0.0729 AC: 106337 AN: 1459436 Hom.: 4296 Cov.: 35 AF XY: 0.0727 AC XY: 52792 AN XY: 725850

African (AFR) AF: 0.0106 AC: 353 AN: 33450

American (AMR) AF: 0.0281 AC: 1255 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2718 AN: 26088

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39672

South Asian (SAS) AF: 0.0600 AC: 5173 AN: 86208

European-Finnish (FIN) AF: 0.144 AC: 7485 AN: 51982

Middle Eastern (MID) AF: 0.0602 AC: 347 AN: 5766

European-Non Finnish (NFE) AF: 0.0765 AC: 85000 AN: 1111290

Other (OTH) AF: 0.0663 AC: 3997 AN: 60316

GnomAD4 genome AF: 0.0566 AC: 8613 AN: 152270 Hom.: 358 Cov.: 34 AF XY: 0.0596 AC XY: 4436 AN XY: 74442

African (AFR) AF: 0.0136 AC: 566 AN: 41572

American (AMR) AF: 0.0415 AC: 635 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0916 AC: 318 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.0590 AC: 285 AN: 4834

European-Finnish (FIN) AF: 0.145 AC: 1542 AN: 10620

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0756 AC: 5141 AN: 67984

Other (OTH) AF: 0.0473 AC: 100 AN: 2116

Alfa AF: 0.0696 Hom.: 185

Bravo AF: 0.0454

Asia WGS AF: 0.0290 AC: 99 AN: 3478

EpiCase AF: 0.0758

EpiControl AF: 0.0710

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	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	-0.52
CADD	Benign	8.4
DANN	Benign	0.87
PhyloP100		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs79899502; hg19: chr16-2140321; COSMIC: COSV51916364; COSMIC: COSV51916364;