16-2088866-C-T

Position:

• chr16-2088866-C-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.*861G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 505,202 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (103 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (36 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0960

Genes affected

TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-2088866-C-T is Benign according to our data. Variant chr16-2088866-C-T is described in ClinVar as [Benign]. Clinvar id is 1230996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.*256C>T		3_prime_UTR_variant	42/42	ENST00000219476.9
PKD1	NM_001009944.3	c.*861G>A		3_prime_UTR_variant	46/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.*256C>T		3_prime_UTR_variant	42/42	5	NM_000548.5
PKD1	ENST00000262304.9	c.*861G>A		3_prime_UTR_variant	46/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 2851 AN: 125572 Hom.: 103 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00827

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00100

Gnomad SAS AF: 0.000221

Gnomad FIN AF: 0.000110

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000568

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.00278 AC: 1056 AN: 379576 Hom.: 36 Cov.: 2 AF XY: 0.00223 AC XY: 444 AN XY: 199358

Gnomad4 AFR exome AF: 0.0678

Gnomad4 AMR exome AF: 0.00620

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000229

Gnomad4 SAS exome AF: 0.000114

Gnomad4 FIN exome AF: 0.0000445

Gnomad4 NFE exome AF: 0.000350

Gnomad4 OTH exome AF: 0.00654

GnomAD4 genome AF: 0.0227 AC: 2853 AN: 125626 Hom.: 103 Cov.: 33 AF XY: 0.0215 AC XY: 1321 AN XY: 61442

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.00826

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00101

Gnomad4 SAS AF: 0.000221

Gnomad4 FIN AF: 0.000110

Gnomad4 NFE AF: 0.000568

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0128 Hom.: 4

Bravo AF: 0.0205

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.9
DANN	Benign	0.57
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2

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: rs78282474; hg19: chr16-2138867;