NM_001009944.3:c.2986-15C>T

Variant names:

• chr16-2112978-G-A
• rs2855349
• NM_001009944.3:c.2986-15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.2986-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,595,606 control chromosomes in the GnomAD database, including 2,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (249 hom., cov: 32)
  • Exomes 𝑓: 0.030 (2505 hom.)
• Consequence: PKD1 NM_001009944.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.570
• Publications: 10 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

ENSG00000261240 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-2112978-G-A is Benign according to our data. Variant chr16-2112978-G-A is described in ClinVar as Benign. ClinVar VariationId is 256939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

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.2986-15C>T		intron	N/A	NP_001009944.3
	PKD1	NM_000296.4		c.2986-15C>T		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.2986-15C>T		intron	N/A	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.2986-15C>T		intron	N/A	ENSP00000399501.1
	PKD1	ENST00000488185.2	TSL:5	c.470+4511C>T		intron	N/A	ENSP00000456672.1

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4461 AN: 152204 Hom.: 242 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0309

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0553 AC: 13227 AN: 239304 AF XY: 0.0594

Gnomad AFR exome AF: 0.0221

Gnomad AMR exome AF: 0.0435

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.235

Gnomad FIN exome AF: 0.00657

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0388

GnomAD4 exome AF: 0.0296 AC: 42663 AN: 1443284 Hom.: 2505 Cov.: 33 AF XY: 0.0331 AC XY: 23798 AN XY: 718578

African (AFR) AF: 0.0232 AC: 774 AN: 33354

American (AMR) AF: 0.0430 AC: 1923 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 356 AN: 26116

East Asian (EAS) AF: 0.199 AC: 7884 AN: 39676

South Asian (SAS) AF: 0.162 AC: 13979 AN: 86122

European-Finnish (FIN) AF: 0.00701 AC: 275 AN: 39246

Middle Eastern (MID) AF: 0.0283 AC: 117 AN: 4132

European-Non Finnish (NFE) AF: 0.0133 AC: 14798 AN: 1109886

Other (OTH) AF: 0.0426 AC: 2557 AN: 60052

GnomAD4 genome AF: 0.0294 AC: 4482 AN: 152322 Hom.: 249 Cov.: 32 AF XY: 0.0321 AC XY: 2393 AN XY: 74474

African (AFR) AF: 0.0221 AC: 920 AN: 41558

American (AMR) AF: 0.0311 AC: 476 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.227 AC: 1177 AN: 5184

South Asian (SAS) AF: 0.171 AC: 827 AN: 4824

European-Finnish (FIN) AF: 0.00612 AC: 65 AN: 10626

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0130 AC: 886 AN: 68028

Other (OTH) AF: 0.0346 AC: 73 AN: 2112

Alfa AF: 0.00826 Hom.: 9

Bravo AF: 0.0291

Asia WGS AF: 0.234 AC: 813 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.025
DANN	Benign	0.72
PhyloP100		-0.57
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2855349; hg19: chr16-2162979; COSMIC: COSV51915841; COSMIC: COSV51915841;