16-2079384-A-G

Variant names:

• chr16-2079384-A-G
• rs371514669
• NM_000548.5:c.3240A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000548.5(TSC2):​c.3240A>G​(p.Leu1080Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 1,586,138 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. L1080L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.704
• Publications: 3 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: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 16-2079384-A-G is Benign according to our data. Variant chr16-2079384-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 413621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.704 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 25 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.3240A>G	p.Leu1080Leu	synonymous	Exon 28 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.3237A>G	p.Leu1079Leu	synonymous	Exon 28 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.3240A>G	p.Leu1080Leu	synonymous	Exon 28 of 41	NP_001107854.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.3240A>G	p.Leu1080Leu	synonymous	Exon 28 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.3240A>G	p.Leu1080Leu	synonymous	Exon 28 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.3108A>G	p.Leu1036Leu	synonymous	Exon 27 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151468 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000174 AC: 25 AN: 1434670 Hom.: 0 Cov.: 31 AF XY: 0.0000196 AC XY: 14 AN XY: 714742

African (AFR) AF: 0.00 AC: 0 AN: 32300

American (AMR) AF: 0.00 AC: 0 AN: 43984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24770

East Asian (EAS) AF: 0.00 AC: 0 AN: 36866

South Asian (SAS) AF: 0.00 AC: 0 AN: 86026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.0000192 AC: 21 AN: 1096570

Other (OTH) AF: 0.0000686 AC: 4 AN: 58350

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151468 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 73966

African (AFR) AF: 0.00 AC: 0 AN: 41280

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5058

South Asian (SAS) AF: 0.00 AC: 0 AN: 4648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67892

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000302

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	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.9
DANN	Benign	0.36
PhyloP100		0.70

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: rs371514669; hg19: chr16-2129385;