rs199569003

Variant names:

• chr16-2104490-C-T
• rs199569003
• NM_001009944.3:c.8161+8G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2104490-C-T
• chr16-2104490-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.8161+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,512,366 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (8 hom., cov: 20)
  • Exomes 𝑓: 0.0060 (58 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, intron
• Scores: Splicing: ADA: 0.0005573
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.45
• 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: 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 (BayesDel_noAF=-0.89).
• BP6: Variant 16-2104490-C-T is Benign according to our data. Variant chr16-2104490-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00547 (810/148004) while in subpopulation NFE AF = 0.00661 (444/67198). AF 95% confidence interval is 0.0061. There are 8 homozygotes in GnomAd4. There are 400 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

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.8161+8G>A		splice_region intron	N/A	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.8161+8G>A		splice_region 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.8161+8G>A		splice_region intron	N/A	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.8161+8G>A		splice_region intron	N/A	ENSP00000399501.1	P98161-3
	PKD1	ENST00000567946.1	TSL:5	c.220+8G>A		splice_region intron	N/A	ENSP00000457984.1	H3BV77

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 810 AN: 147892 Hom.: 8 Cov.: 20

Gnomad AFR AF: 0.00110

Gnomad AMI AF: 0.00553

Gnomad AMR AF: 0.00601

Gnomad ASJ AF: 0.00524

Gnomad EAS AF: 0.000203

Gnomad SAS AF: 0.00387

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00661

Gnomad OTH AF: 0.00541

GnomAD2 exomes AF: 0.00539 AC: 815 AN: 151340 AF XY: 0.00542

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.00348

Gnomad ASJ exome AF: 0.00335

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.00706

Gnomad OTH exome AF: 0.00551

GnomAD4 exome AF: 0.00603 AC: 8221 AN: 1364362 Hom.: 58 Cov.: 28 AF XY: 0.00593 AC XY: 4005 AN XY: 675900

African (AFR) AF: 0.00109 AC: 33 AN: 30164

American (AMR) AF: 0.00382 AC: 140 AN: 36682

Ashkenazi Jewish (ASJ) AF: 0.00269 AC: 67 AN: 24922

East Asian (EAS) AF: 0.00 AC: 0 AN: 36780

South Asian (SAS) AF: 0.00451 AC: 358 AN: 79410

European-Finnish (FIN) AF: 0.0130 AC: 557 AN: 42782

Middle Eastern (MID) AF: 0.00273 AC: 11 AN: 4026

European-Non Finnish (NFE) AF: 0.00647 AC: 6809 AN: 1052816

Other (OTH) AF: 0.00433 AC: 246 AN: 56780

GnomAD4 genome AF: 0.00547 AC: 810 AN: 148004 Hom.: 8 Cov.: 20 AF XY: 0.00554 AC XY: 400 AN XY: 72202

African (AFR) AF: 0.00110 AC: 43 AN: 39132

American (AMR) AF: 0.00600 AC: 90 AN: 15004

Ashkenazi Jewish (ASJ) AF: 0.00524 AC: 18 AN: 3436

East Asian (EAS) AF: 0.000204 AC: 1 AN: 4914

South Asian (SAS) AF: 0.00388 AC: 18 AN: 4642

European-Finnish (FIN) AF: 0.0173 AC: 180 AN: 10428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00661 AC: 444 AN: 67198

Other (OTH) AF: 0.00535 AC: 11 AN: 2056

Alfa AF: 0.00573 Hom.: 2

Bravo AF: 0.00442

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	not provided (1)
-	-	1	PKD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.0
DANN	Benign	0.93
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.030
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: rs199569003; hg19: chr16-2154491;