16-2088583-G-C

Variant names:

• chr16-2088583-G-C
• rs1051771
• NM_000548.5:c.5397G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000548.5(TSC2):​c.5397G>C​(p.Ser1799Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,607,436 control chromosomes in the GnomAD database, including 6,704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1799S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.065 (441 hom., cov: 33)
  • Exomes 𝑓: 0.088 (6263 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: -15.5
• Publications: 33 publications found

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]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 16-2088583-G-C is Benign according to our data. Variant chr16-2088583-G-C is described in ClinVar as Benign. ClinVar VariationId is 49847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-15.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0897 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.5397G>C	p.Ser1799Ser	synonymous	Exon 42 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.5394G>C	p.Ser1798Ser	synonymous	Exon 42 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.5328G>C	p.Ser1776Ser	synonymous	Exon 41 of 41	NP_001107854.1	P49815-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.5397G>C	p.Ser1799Ser	synonymous	Exon 42 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.5328G>C	p.Ser1776Ser	synonymous	Exon 41 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.5196G>C	p.Ser1732Ser	synonymous	Exon 40 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.0651 AC: 9907 AN: 152162 Hom.: 441 Cov.: 33

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0517

Gnomad ASJ AF: 0.0827

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0578

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0916

Gnomad OTH AF: 0.0598

GnomAD2 exomes AF: 0.0723 AC: 17663 AN: 244322 AF XY: 0.0747

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.0332

Gnomad ASJ exome AF: 0.0935

Gnomad EAS exome AF: 0.000329

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.0952

Gnomad OTH exome AF: 0.0744

GnomAD4 exome AF: 0.0884 AC: 128580 AN: 1455156 Hom.: 6263 Cov.: 33 AF XY: 0.0877 AC XY: 63544 AN XY: 724158

African (AFR) AF: 0.0141 AC: 471 AN: 33466

American (AMR) AF: 0.0344 AC: 1536 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0947 AC: 2474 AN: 26134

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39698

South Asian (SAS) AF: 0.0580 AC: 5006 AN: 86238

European-Finnish (FIN) AF: 0.141 AC: 6648 AN: 47002

Middle Eastern (MID) AF: 0.0550 AC: 317 AN: 5766

European-Non Finnish (NFE) AF: 0.0964 AC: 107195 AN: 1111824

Other (OTH) AF: 0.0816 AC: 4925 AN: 60328

GnomAD4 genome AF: 0.0650 AC: 9904 AN: 152280 Hom.: 441 Cov.: 33 AF XY: 0.0665 AC XY: 4947 AN XY: 74446

African (AFR) AF: 0.0170 AC: 707 AN: 41576

American (AMR) AF: 0.0517 AC: 792 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0827 AC: 287 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.0576 AC: 278 AN: 4824

European-Finnish (FIN) AF: 0.136 AC: 1446 AN: 10598

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0916 AC: 6228 AN: 68012

Other (OTH) AF: 0.0592 AC: 125 AN: 2112

Alfa AF: 0.0467 Hom.: 58

Bravo AF: 0.0558

EpiCase AF: 0.0914

EpiControl AF: 0.0818

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	4	Tuberous sclerosis 2 (4)
-	-	3	not provided (3)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.0020
DANN	Benign	0.65
PhyloP100		-15
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: rs1051771; hg19: chr16-2138584; COSMIC: COSV99238392;