rs779122170

Variant names:

• chr16-2084578-G-A
• rs779122170
• NM_000548.5:c.4356G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2084578-G-A
• chr16-2084578-G-C
• chr16-2084578-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000548.5(TSC2):​c.4356G>A​(p.Ser1452Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,454,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1452S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.04
• Publications: 0 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]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-2084578-G-A is Benign according to our data. Variant chr16-2084578-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 413727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 66 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.4356G>A	p.Ser1452Ser	synonymous	Exon 34 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.4353G>A	p.Ser1451Ser	synonymous	Exon 34 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.4287G>A	p.Ser1429Ser	synonymous	Exon 33 of 41	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.4356G>A	p.Ser1452Ser	synonymous	Exon 34 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.4287G>A	p.Ser1429Ser	synonymous	Exon 33 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.4155G>A	p.Ser1385Ser	synonymous	Exon 32 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000417 AC: 10 AN: 239596 AF XY: 0.0000456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000729

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000454 AC: 66 AN: 1454398 Hom.: 0 Cov.: 33 AF XY: 0.0000401 AC XY: 29 AN XY: 723848

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000672 AC: 3 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1111630

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Tuberous sclerosis 2 (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)
-	-	1	not provided (1)
-	-	1	TSC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.3
DANN	Benign	0.93
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs779122170; hg19: chr16-2134579; COSMIC: COSV51911836; COSMIC: COSV51911836;