rs3209986

Variant names:

• chr16-2090553-G-A
• rs3209986
• NM_001009944.3:c.12176C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2090553-G-A
• chr16-2090553-G-C

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.12176C>T​(p.Ala4059Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0715 in 1,609,152 control chromosomes in the GnomAD database, including 4,643 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (360 hom., cov: 34)
  • Exomes 𝑓: 0.073 (4283 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.236
• Publications: 29 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=0.0025211573).
• BP6: Variant 16-2090553-G-A is Benign according to our data. Variant chr16-2090553-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.074 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.12176C>T	p.Ala4059Val	missense	Exon 45 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.12173C>T	p.Ala4058Val	missense	Exon 45 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.12176C>T	p.Ala4059Val	missense	Exon 45 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.12173C>T	p.Ala4058Val	missense	Exon 45 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000472577.1	TSL:2	n.204C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0574 AC: 8730 AN: 152174 Hom.: 360 Cov.: 34

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0448

Gnomad ASJ AF: 0.0916

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0593

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0758

Gnomad OTH AF: 0.0497

GnomAD2 exomes AF: 0.0645 AC: 15475 AN: 239776 AF XY: 0.0672

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.0281

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.000276

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.0793

Gnomad OTH exome AF: 0.0674

GnomAD4 exome AF: 0.0730 AC: 106370 AN: 1456860 Hom.: 4283 Cov.: 35 AF XY: 0.0729 AC XY: 52833 AN XY: 724778

African (AFR) AF: 0.0120 AC: 400 AN: 33438

American (AMR) AF: 0.0290 AC: 1295 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2736 AN: 26114

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39658

South Asian (SAS) AF: 0.0599 AC: 5164 AN: 86144

European-Finnish (FIN) AF: 0.143 AC: 7101 AN: 49610

Middle Eastern (MID) AF: 0.0617 AC: 353 AN: 5724

European-Non Finnish (NFE) AF: 0.0767 AC: 85273 AN: 1111286

Other (OTH) AF: 0.0670 AC: 4040 AN: 60306

GnomAD4 genome AF: 0.0573 AC: 8725 AN: 152292 Hom.: 360 Cov.: 34 AF XY: 0.0603 AC XY: 4492 AN XY: 74440

African (AFR) AF: 0.0147 AC: 610 AN: 41572

American (AMR) AF: 0.0448 AC: 685 AN: 15304

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

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.0592 AC: 286 AN: 4832

European-Finnish (FIN) AF: 0.145 AC: 1543 AN: 10608

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0758 AC: 5152 AN: 68006

Other (OTH) AF: 0.0491 AC: 104 AN: 2116

Alfa AF: 0.0723 Hom.: 539

Bravo AF: 0.0464

TwinsUK AF: 0.0825 AC: 306

ALSPAC AF: 0.0778 AC: 300

ESP6500AA AF: 0.0144 AC: 63

ESP6500EA AF: 0.0804 AC: 690

ExAC AF: 0.0657 AC: 7918

Asia WGS AF: 0.0290 AC: 101 AN: 3478

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)
-	-	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
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.5
DANN	Benign	0.82
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.24
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.091
Sift	Benign	0.20	T
Sift4G	Uncertain	0.050	T
Polyphen		0.015	B
Vest4		0.14
ClinPred		0.00081	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.040
gMVP		0.33
Mutation Taster		=96/4	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: rs3209986; hg19: chr16-2140554; COSMIC: COSV51916377; COSMIC: COSV51916377;