rs780284563

Variant names:

• chr16-2100060-G-C
• rs780284563
• NM_001009944.3:c.9724C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2100060-G-C
• chr16-2100060-G-A
• chr16-2100060-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001009944.3(PKD1):​c.9724C>G​(p.Leu3242Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000761 in 1,445,386 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (1 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.05
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.9724C>G	p.Leu3242Val	missense	Exon 29 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.9724C>G	p.Leu3242Val	missense	Exon 29 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.9724C>G	p.Leu3242Val	missense	Exon 29 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.9724C>G	p.Leu3242Val	missense	Exon 29 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000480227.5	TSL:1	n.1461C>G		non_coding_transcript_exon	Exon 7 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000271 AC: 6 AN: 221164 AF XY: 0.0000249

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000192

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000761 AC: 11 AN: 1445386 Hom.: 1 Cov.: 32 AF XY: 0.00000557 AC XY: 4 AN XY: 718126

African (AFR) AF: 0.00 AC: 0 AN: 33084

American (AMR) AF: 0.000238 AC: 10 AN: 42026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25802

East Asian (EAS) AF: 0.00 AC: 0 AN: 38918

South Asian (SAS) AF: 0.00 AC: 0 AN: 84790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105702

Other (OTH) AF: 0.0000168 AC: 1 AN: 59674

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.00000835 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Polycystic kidney disease, adult type (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	0.16
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.0
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.093	T
Polyphen		1.0	D
Vest4		0.33
MutPred		0.34		Gain of sheet (P = 0.0085)
MVP		0.82
ClinPred		0.44	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.63
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs780284563; hg19: chr16-2150061;