16-2088868-C-T

Position:

• chr16-2088868-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.*859G>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 0.129 in 521,830 control chromosomes in the GnomAD database, including 7,701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4787 hom., cov: 32)
  • Exomes 𝑓: 0.099 (2914 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=-0.82).
• BP6: Variant 16-2088868-C-T is Benign according to our data. Variant chr16-2088868-C-T is described in ClinVar as [Benign]. Clinvar id is 1245044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.*258C>T		3_prime_UTR_variant	42/42	ENST00000219476.9
PKD1	NM_001009944.3	c.*859G>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.*258C>T		3_prime_UTR_variant	42/42	5	NM_000548.5
PKD1	ENST00000262304.9	c.*859G>A		3_prime_UTR_variant	46/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.207 AC: 29754 AN: 143528 Hom.: 4776 Cov.: 32

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.000801

Gnomad SAS AF: 0.0337

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.190

GnomAD4 exome AF: 0.0991 AC: 37461 AN: 378198 Hom.: 2914 Cov.: 3 AF XY: 0.0939 AC XY: 18658 AN XY: 198660

Gnomad4 AFR exome AF: 0.435

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.0000382

Gnomad4 SAS exome AF: 0.0346

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.207 AC: 29800 AN: 143632 Hom.: 4787 Cov.: 32 AF XY: 0.203 AC XY: 14251 AN XY: 70124

Gnomad4 AFR AF: 0.469

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.000803

Gnomad4 SAS AF: 0.0335

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.188

Alfa AF: 0.123 Hom.: 1606

Bravo AF: 0.214

Asia WGS AF: 0.0420 AC: 147 AN: 3474

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 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.6
DANN	Benign	0.56
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: rs13332377; hg19: chr16-2138869;