rs9925969

Variant names:

• chr16-2102386-A-G
• rs9925969
• NM_001009944.3:c.9196T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2102386-A-G
• chr16-2102386-A-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.9196T>C​(p.Phe3066Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,555,320 control chromosomes in the GnomAD database, including 27,908 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (6324 hom., cov: 33)
  • Exomes 𝑓: 0.16 (21584 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.610
• Publications: 12 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]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.9981813E-4).
• BP6: Variant 16-2102386-A-G is Benign according to our data. Variant chr16-2102386-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.476 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.9196T>C	p.Phe3066Leu	missense	Exon 25 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.9196T>C	p.Phe3066Leu	missense	Exon 25 of 46	NP_000287.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.9196T>C	p.Phe3066Leu	missense	Exon 25 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.9196T>C	p.Phe3066Leu	missense	Exon 25 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000480227.5	TSL:1	n.933T>C		non_coding_transcript_exon	Exon 3 of 8

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37355 AN: 151628 Hom.: 6305 Cov.: 33

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0702

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.232

GnomAD2 exomes AF: 0.156 AC: 24737 AN: 158300 AF XY: 0.149

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.000260

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.164 AC: 229760 AN: 1403576 Hom.: 21584 Cov.: 35 AF XY: 0.160 AC XY: 111113 AN XY: 693318

African (AFR) AF: 0.495 AC: 15755 AN: 31826

American (AMR) AF: 0.127 AC: 4617 AN: 36238

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 5953 AN: 25218

East Asian (EAS) AF: 0.000436 AC: 16 AN: 36684

South Asian (SAS) AF: 0.0747 AC: 6000 AN: 80368

European-Finnish (FIN) AF: 0.181 AC: 8789 AN: 48564

Middle Eastern (MID) AF: 0.229 AC: 933 AN: 4068

European-Non Finnish (NFE) AF: 0.164 AC: 177416 AN: 1082414

Other (OTH) AF: 0.177 AC: 10281 AN: 58196

GnomAD4 genome AF: 0.247 AC: 37418 AN: 151744 Hom.: 6324 Cov.: 33 AF XY: 0.241 AC XY: 17870 AN XY: 74210

African (AFR) AF: 0.482 AC: 19828 AN: 41168

American (AMR) AF: 0.184 AC: 2803 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 803 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5176

South Asian (SAS) AF: 0.0697 AC: 336 AN: 4824

European-Finnish (FIN) AF: 0.188 AC: 1986 AN: 10578

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11007 AN: 67946

Other (OTH) AF: 0.229 AC: 483 AN: 2108

Alfa AF: 0.156 Hom.: 720

Bravo AF: 0.259

ESP6500AA AF: 0.315 AC: 1321

ESP6500EA AF: 0.0838 AC: 698

ExAC AF: 0.121 AC: 12389

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.2
DANN	Benign	0.86
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.00070	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.61
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.085
Sift	Benign	0.66	T
Sift4G	Benign	0.16	T
Polyphen		0.21	B
Vest4		0.14
MutPred		0.44		Gain of sheet (P = 0.0344)
ClinPred		0.0099	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.43
Mutation Taster		=90/10	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: rs9925969; hg19: chr16-2152387; COSMIC: COSV51923506; COSMIC: COSV51923506;