rs13333553

Variant names:

• chr16-2103413-A-T
• rs13333553
• NM_001009944.3:c.8644T>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2103413-A-T
• chr16-2103413-A-G

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.8644T>A​(p.Trp2882Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 1,599,366 control chromosomes in the GnomAD database, including 1,050 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (553 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (497 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.124
• Publications: 8 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=0.0021344721).
• BP6: Variant 16-2103413-A-T is Benign according to our data. Variant chr16-2103413-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 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.8644T>A	p.Trp2882Arg	missense	Exon 23 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8644T>A	p.Trp2882Arg	missense	Exon 23 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.8644T>A	p.Trp2882Arg	missense	Exon 23 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8644T>A	p.Trp2882Arg	missense	Exon 23 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000480227.5	TSL:1	n.381T>A		non_coding_transcript_exon	Exon 1 of 8

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7130 AN: 152152 Hom.: 553 Cov.: 31

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0363

GnomAD2 exomes AF: 0.0118 AC: 2759 AN: 233310 AF XY: 0.00872

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.00896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.00409

GnomAD4 exome AF: 0.00476 AC: 6894 AN: 1447096 Hom.: 497 Cov.: 34 AF XY: 0.00396 AC XY: 2853 AN XY: 720446

African (AFR) AF: 0.163 AC: 5434 AN: 33392

American (AMR) AF: 0.0103 AC: 461 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.000418 AC: 36 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41218

Middle Eastern (MID) AF: 0.00629 AC: 26 AN: 4136

European-Non Finnish (NFE) AF: 0.000247 AC: 275 AN: 1111590

Other (OTH) AF: 0.0110 AC: 660 AN: 60108

GnomAD4 genome AF: 0.0469 AC: 7139 AN: 152270 Hom.: 553 Cov.: 31 AF XY: 0.0450 AC XY: 3350 AN XY: 74472

African (AFR) AF: 0.161 AC: 6690 AN: 41534

American (AMR) AF: 0.0218 AC: 334 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68026

Other (OTH) AF: 0.0360 AC: 76 AN: 2114

Alfa AF: 0.0190 Hom.: 43

Bravo AF: 0.0536

ESP6500AA AF: 0.130 AC: 515

ESP6500EA AF: 0.000770 AC: 6

ExAC AF: 0.0137 AC: 1602

Asia WGS AF: 0.00895 AC: 31 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.1
DANN	Benign	0.46
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.12
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.076
Sift	Benign	0.37	T
Sift4G	Benign	0.46	T
Polyphen		0.054	B
Vest4		0.10
MutPred		0.46		Gain of disorder (P = 0.0026)
ClinPred		0.00031	T
GERP RS		2.6
Varity_R		0.034
gMVP		0.55
Mutation Taster		=91/9	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: rs13333553; hg19: chr16-2153414; COSMIC: COSV51920157; COSMIC: COSV51920157;