16-2091177-G-T

Variant names:

• chr16-2091177-G-T
• rs754015180
• NM_001009944.3:c.11713-3C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000262304.9(PKD1):​c.11713-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 ENST00000262304.9 splice_region, intron
• Scores: Splicing: ADA: 0.9839
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13
• 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: ClinGen, Orphanet
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262304.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.11713-3C>A		splice_region intron	N/A	NP_001009944.3
	PKD1	NM_000296.4		c.11710-3C>A		splice_region intron	N/A	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.11713-3C>A		splice_region intron	N/A	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.11710-3C>A		splice_region intron	N/A	ENSP00000399501.1
	PKD1	ENST00000487932.5	TSL:5	n.*2906-3C>A		splice_region intron	N/A	ENSP00000457132.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1271422 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 625772

African (AFR) AF: 0.00 AC: 0 AN: 24718

American (AMR) AF: 0.00 AC: 0 AN: 18910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18918

East Asian (EAS) AF: 0.00 AC: 0 AN: 27564

South Asian (SAS) AF: 0.00 AC: 0 AN: 64996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3592

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1029380

Other (OTH) AF: 0.00 AC: 0 AN: 51532

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.74
PhyloP100		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs754015180; hg19: chr16-2141178;