rs146887330

Variant names:

• chr16-2111665-G-A
• rs146887330
• NM_001009944.3:c.3502C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2111665-G-A
• chr16-2111665-G-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.3502C>T​(p.Pro1168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,574,942 control chromosomes in the GnomAD database, including 312 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 0.013 (21 hom., cov: 33)
  • Exomes 𝑓: 0.018 (291 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.458
• Publications: 16 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001009944.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0032174885).
• BP6: Variant 16-2111665-G-A is Benign according to our data. Variant chr16-2111665-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0132 (2005/152250) while in subpopulation NFE AF = 0.0195 (1327/67990). AF 95% confidence interval is 0.0186. There are 21 homozygotes in GnomAd4. There are 988 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

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.3502C>T	p.Pro1168Ser	missense	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.3502C>T	p.Pro1168Ser	missense	Exon 15 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.3502C>T	p.Pro1168Ser	missense	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.3502C>T	p.Pro1168Ser	missense	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-3307C>T		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2005 AN: 152132 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0143 AC: 2619 AN: 183752 AF XY: 0.0146

Gnomad AFR exome AF: 0.00280

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.00992

GnomAD4 exome AF: 0.0182 AC: 25844 AN: 1422692 Hom.: 291 Cov.: 36 AF XY: 0.0177 AC XY: 12460 AN XY: 704446

African (AFR) AF: 0.00251 AC: 82 AN: 32694

American (AMR) AF: 0.00449 AC: 175 AN: 38990

Ashkenazi Jewish (ASJ) AF: 0.0198 AC: 505 AN: 25458

East Asian (EAS) AF: 0.00 AC: 0 AN: 37798

South Asian (SAS) AF: 0.00934 AC: 765 AN: 81918

European-Finnish (FIN) AF: 0.0285 AC: 1407 AN: 49300

Middle Eastern (MID) AF: 0.00147 AC: 6 AN: 4092

European-Non Finnish (NFE) AF: 0.0202 AC: 22119 AN: 1093696

Other (OTH) AF: 0.0134 AC: 785 AN: 58746

GnomAD4 genome AF: 0.0132 AC: 2005 AN: 152250 Hom.: 21 Cov.: 33 AF XY: 0.0133 AC XY: 988 AN XY: 74436

African (AFR) AF: 0.00289 AC: 120 AN: 41556

American (AMR) AF: 0.00320 AC: 49 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4828

European-Finnish (FIN) AF: 0.0350 AC: 372 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0195 AC: 1327 AN: 67990

Other (OTH) AF: 0.0162 AC: 34 AN: 2104

Alfa AF: 0.0128 Hom.: 15

Bravo AF: 0.0107

ESP6500AA AF: 0.00376 AC: 16

ESP6500EA AF: 0.0142 AC: 120

ExAC AF: 0.0112 AC: 1316

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.3
DANN	Benign	0.93
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L
PhyloP100		0.46
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.068
Sift	Benign	0.38	T
Sift4G	Benign	0.27	T
Polyphen		0.21	B
Vest4		0.092
ClinPred		0.0030	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.074
gMVP		0.27
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs146887330; hg19: chr16-2161666; COSMIC: COSV108051948; COSMIC: COSV108051948;