16-2104493-G-C

Variant names:

• chr16-2104493-G-C
• rs534696523
• NM_001009944.3:c.8161+5C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001009944.3(PKD1):​c.8161+5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 1,368,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004490
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.8161+5C>G		splice_region intron	N/A	NP_001009944.3
	PKD1	NM_000296.4		c.8161+5C>G		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.8161+5C>G		splice_region intron	N/A	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.8161+5C>G		splice_region intron	N/A	ENSP00000399501.1
	PKD1	ENST00000567946.1	TSL:5	c.220+5C>G		splice_region intron	N/A	ENSP00000457984.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000438 AC: 6 AN: 1368426 Hom.: 0 Cov.: 28 AF XY: 0.00000738 AC XY: 5 AN XY: 677672

African (AFR) AF: 0.00 AC: 0 AN: 30330

American (AMR) AF: 0.0000272 AC: 1 AN: 36764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24956

East Asian (EAS) AF: 0.00 AC: 0 AN: 36836

South Asian (SAS) AF: 0.00 AC: 0 AN: 79516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4030

European-Non Finnish (NFE) AF: 0.00000474 AC: 5 AN: 1055524

Other (OTH) AF: 0.00 AC: 0 AN: 56912

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.30
DANN	Benign	0.40
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.0		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: rs534696523; hg19: chr16-2154494;