16-2088887-AC-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001009944.3(PKD1):c.*839del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00956 in 387,146 control chromosomes in the GnomAD database, including 135 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (104 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (31 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.723

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 -10 ACMG points.

• BP6: Variant 16-2088887-AC-A is Benign according to our data. Variant chr16-2088887-AC-A is described in ClinVar as [Benign]. Clinvar id is 1242684.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.*278del		3_prime_UTR_variant	42/42	ENST00000219476.9
PKD1	NM_001009944.3	c.*839del		3_prime_UTR_variant	46/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.*278del		3_prime_UTR_variant	42/42	5	NM_000548.5
PKD1	ENST00000262304.9	c.*839del		3_prime_UTR_variant	46/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 2845 AN: 131758 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.0670

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00776

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000230

Gnomad FIN AF: 0.000119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000621

Gnomad OTH AF: 0.0173

GnomAD4 exome AF: 0.00335 AC: 854 AN: 255266 Hom.: 31 Cov.: 0 AF XY: 0.00271 AC XY: 365 AN XY: 134832

Gnomad4 AFR exome AF: 0.0692

Gnomad4 AMR exome AF: 0.00708

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000885

Gnomad4 FIN exome AF: 0.0000775

Gnomad4 NFE exome AF: 0.000371

Gnomad4 OTH exome AF: 0.00762

GnomAD4 genome AF: 0.0216 AC: 2846 AN: 131880 Hom.: 104 Cov.: 32 AF XY: 0.0204 AC XY: 1317 AN XY: 64628

Gnomad4 AFR AF: 0.0668

Gnomad4 AMR AF: 0.00775

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000231

Gnomad4 FIN AF: 0.000119

Gnomad4 NFE AF: 0.000621

Gnomad4 OTH AF: 0.0171

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs200372958; hg19: chr16-2138888;