chr16-2071883-G-A

Variant names:

• chr16-2071883-G-A
• rs749536123
• NM_000548.5:c.2046G>A

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.2046G>A​(p.Gly682Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,597,462 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. G682G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.617
• Publications: 2 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-2071883-G-A is Benign according to our data. Variant chr16-2071883-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 237978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.617 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 18 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.2046G>A	p.Gly682Gly	synonymous	Exon 19 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.2046G>A	p.Gly682Gly	synonymous	Exon 19 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.2046G>A	p.Gly682Gly	synonymous	Exon 19 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.2046G>A	p.Gly682Gly	synonymous	Exon 19 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.2046G>A	p.Gly682Gly	synonymous	Exon 19 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.2046G>A	p.Gly682Gly	synonymous	Exon 19 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 6 AN: 216030 AF XY: 0.0000253

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000125 AC: 18 AN: 1445214 Hom.: 0 Cov.: 33 AF XY: 0.0000111 AC XY: 8 AN XY: 717582

African (AFR) AF: 0.00 AC: 0 AN: 33136

American (AMR) AF: 0.000116 AC: 5 AN: 42990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25742

East Asian (EAS) AF: 0.00 AC: 0 AN: 38880

South Asian (SAS) AF: 0.00 AC: 0 AN: 83736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.0000109 AC: 12 AN: 1104728

Other (OTH) AF: 0.0000168 AC: 1 AN: 59688

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152248 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74388

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

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	not specified (1)
-	-	1	TSC2-related disorder (1)
-	-	1	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.6
DANN	Benign	0.83
PhyloP100		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749536123; hg19: chr16-2121884;