rs2855349

chr16-2112978-G-Achr16-2112978-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):c.2986-15C>T variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.570

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 256939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2112978-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.2986-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.2986-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001009944.3	P5
	ENST00000568795.1	n.161-69G>A		intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.0553 AC: 13227 AN: 239304 Hom.: 1054 AF XY: 0.0594 AC XY: 7758 AN XY: 130648

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 SAS exome AF: 0.168

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

Gnomad4 AFR exome AF: 0.0232

Gnomad4 AMR exome AF: 0.0430

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.199

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.00701

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0426

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

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.0311

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.227

Gnomad4 SAS AF: 0.171

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.00826 Hom.: 9

Bravo AF: 0.0291

Asia WGS AF: 0.234 AC: 813 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 20, 2020

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Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The c.2986-15C>T, p.? variant was identified in 5.3% of 6391 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

Autosomal dominant polycystic kidney disease Benign:1

Benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.025
Dann	Benign	0.72
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4

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

Publications

LitVar

Other links and lift over

dbSNP: rs2855349; hg19: chr16-2162979; COSMIC: COSV51915841; COSMIC: COSV51915841;