16-2086841-C-T

Variant names:

• chr16-2086841-C-T
• rs45517384
• NM_000548.5:c.4959C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000548.5(TSC2):​c.4959C>T​(p.Ser1653Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,603,860 control chromosomes in the GnomAD database, including 158 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. S1653S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0098 (16 hom., cov: 33)
  • Exomes 𝑓: 0.012 (142 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22 O:2
• Conservation: PhyloP100: -2.92
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-2086841-C-T is Benign according to our data. Variant chr16-2086841-C-T is described in ClinVar as Benign. ClinVar VariationId is 49818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.92 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00983 (1497/152326) while in subpopulation NFE AF = 0.014 (954/68032). AF 95% confidence interval is 0.0133. There are 16 homozygotes in GnomAd4. There are 748 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1497 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.4959C>T	p.Ser1653Ser	synonymous	Exon 38 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.4956C>T	p.Ser1652Ser	synonymous	Exon 38 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.4890C>T	p.Ser1630Ser	synonymous	Exon 37 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.4959C>T	p.Ser1653Ser	synonymous	Exon 38 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.4890C>T	p.Ser1630Ser	synonymous	Exon 37 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4758C>T	p.Ser1586Ser	synonymous	Exon 36 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00985 AC: 1499 AN: 152208 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00955 AC: 2217 AN: 232198 AF XY: 0.00962

Gnomad AFR exome AF: 0.00276

Gnomad AMR exome AF: 0.00666

Gnomad ASJ exome AF: 0.000415

Gnomad EAS exome AF: 0.000349

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0122 AC: 17657 AN: 1451534 Hom.: 142 Cov.: 31 AF XY: 0.0117 AC XY: 8443 AN XY: 721418

African (AFR) AF: 0.00187 AC: 62 AN: 33222

American (AMR) AF: 0.00799 AC: 349 AN: 43694

Ashkenazi Jewish (ASJ) AF: 0.000500 AC: 13 AN: 25982

East Asian (EAS) AF: 0.000230 AC: 9 AN: 39162

South Asian (SAS) AF: 0.00144 AC: 122 AN: 84988

European-Finnish (FIN) AF: 0.0181 AC: 929 AN: 51404

Middle Eastern (MID) AF: 0.00350 AC: 18 AN: 5150

European-Non Finnish (NFE) AF: 0.0140 AC: 15505 AN: 1107996

Other (OTH) AF: 0.0108 AC: 650 AN: 59936

GnomAD4 genome AF: 0.00983 AC: 1497 AN: 152326 Hom.: 16 Cov.: 33 AF XY: 0.0100 AC XY: 748 AN XY: 74490

African (AFR) AF: 0.00236 AC: 98 AN: 41564

American (AMR) AF: 0.0139 AC: 212 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.0180 AC: 191 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 954 AN: 68032

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.00677 Hom.: 5

Bravo AF: 0.00954

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	5	Tuberous sclerosis 2 (5)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)
-	-	-	Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.14
DANN	Benign	0.83
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs45517384; hg19: chr16-2136842; COSMIC: COSV99238302;