16-2084993-C-T

Variant names:

• chr16-2084993-C-T
• rs35986575
• NM_000548.5:c.4536C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000548.5(TSC2):​c.4536C>T​(p.Asp1512Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00377 in 1,613,256 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0039 (16 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23 O:2
• Conservation: PhyloP100: -1.03
• Publications: 6 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 16-2084993-C-T is Benign according to our data. Variant chr16-2084993-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00284 (432/152324) while in subpopulation NFE AF = 0.00398 (271/68016). AF 95% confidence interval is 0.00359. There are 3 homozygotes in GnomAd4. There are 202 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 432 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.4536C>T	p.Asp1512Asp	synonymous	Exon 35 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.4533C>T	p.Asp1511Asp	synonymous	Exon 35 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.4467C>T	p.Asp1489Asp	synonymous	Exon 34 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.4536C>T	p.Asp1512Asp	synonymous	Exon 35 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.4467C>T	p.Asp1489Asp	synonymous	Exon 34 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4335C>T	p.Asp1445Asp	synonymous	Exon 33 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 432 AN: 152206 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00310 AC: 775 AN: 250290 AF XY: 0.00330

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.0208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00386 AC: 5646 AN: 1460932 Hom.: 16 Cov.: 33 AF XY: 0.00395 AC XY: 2870 AN XY: 726768

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.00116 AC: 52 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 543 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00255 AC: 220 AN: 86258

European-Finnish (FIN) AF: 0.00221 AC: 116 AN: 52540

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00403 AC: 4482 AN: 1111958

Other (OTH) AF: 0.00358 AC: 216 AN: 60378

GnomAD4 genome AF: 0.00284 AC: 432 AN: 152324 Hom.: 3 Cov.: 34 AF XY: 0.00271 AC XY: 202 AN XY: 74488

African (AFR) AF: 0.000938 AC: 39 AN: 41570

American (AMR) AF: 0.00104 AC: 16 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4832

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00398 AC: 271 AN: 68016

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00403 Hom.: 4

Bravo AF: 0.00276

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	6	not specified (6)
-	-	5	Tuberous sclerosis 2 (5)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Tuberous sclerosis syndrome;C0349649:Lung lymphangioleiomyomatosis (1)
-	-	-	Lymphangiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.27
DANN	Benign	0.77
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs35986575; hg19: chr16-2134994;