chr16-2091176-T-C

Variant names:

• chr16-2091176-T-C
• rs1555445274
• NM_001009944.3:c.11713-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001009944.3(PKD1):​c.11713-2A>G variant causes a splice acceptor, 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 pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 NM_001009944.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.52
• Publications: 1 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.022537176 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.3, offset of -35, new splice context is: gcagggccccgccccggcAGcgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2091176-T-C is Pathogenic according to our data. Variant chr16-2091176-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 447955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.11713-2A>G		splice_acceptor intron	N/A	NP_001009944.3
	PKD1	NM_000296.4		c.11710-2A>G		splice_acceptor intron	N/A	NP_000287.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.11713-2A>G		splice_acceptor intron	N/A	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.11710-2A>G		splice_acceptor intron	N/A	ENSP00000399501.1
	PKD1	ENST00000487932.5	TSL:5	n.*2906-2A>G		splice_acceptor 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: 1199326 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 589168

African (AFR) AF: 0.00 AC: 0 AN: 23304

American (AMR) AF: 0.00 AC: 0 AN: 16686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17050

East Asian (EAS) AF: 0.00 AC: 0 AN: 19850

South Asian (SAS) AF: 0.00 AC: 0 AN: 64530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3254

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 984884

Other (OTH) AF: 0.00 AC: 0 AN: 47068

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	PKD1-related disorder (1)
1	-	-	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	26
DANN	Benign	0.95
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.72	D
PhyloP100		1.5
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.97		Position offset: -2

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

Other links and lift over

dbSNP: rs1555445274; hg19: chr16-2141177;