chr16-2058754-A-G

Variant names:

• chr16-2058754-A-G
• rs1800748
• NM_000548.5:c.856A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.856A>G​(p.Met286Val) variant causes a missense change. The variant allele was found at a frequency of 0.00109 in 1,582,982 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M286L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (13 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23 O:2
• Conservation: PhyloP100: 4.60
• Publications: 34 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 33 uncertain in NM_000548.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.00816381).
• BP6: Variant 16-2058754-A-G is Benign according to our data. Variant chr16-2058754-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 50009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00112 (170/152274) while in subpopulation EAS AF = 0.021 (109/5190). AF 95% confidence interval is 0.0178. There are 3 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 170 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.856A>G	p.Met286Val	missense	Exon 10 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.856A>G	p.Met286Val	missense	Exon 10 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.856A>G	p.Met286Val	missense	Exon 10 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.856A>G	p.Met286Val	missense	Exon 10 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.856A>G	p.Met286Val	missense	Exon 10 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.856A>G	p.Met286Val	missense	Exon 10 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152156 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00186 AC: 374 AN: 200760 AF XY: 0.00177

Gnomad AFR exome AF: 0.0000789

Gnomad AMR exome AF: 0.000105

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.0187

Gnomad FIN exome AF: 0.000223

Gnomad NFE exome AF: 0.000637

Gnomad OTH exome AF: 0.00173

GnomAD4 exome AF: 0.00108 AC: 1552 AN: 1430708 Hom.: 13 Cov.: 32 AF XY: 0.00108 AC XY: 766 AN XY: 708534

African (AFR) AF: 0.0000905 AC: 3 AN: 33158

American (AMR) AF: 0.0000761 AC: 3 AN: 39446

Ashkenazi Jewish (ASJ) AF: 0.0000786 AC: 2 AN: 25446

East Asian (EAS) AF: 0.0181 AC: 701 AN: 38826

South Asian (SAS) AF: 0.000743 AC: 61 AN: 82052

European-Finnish (FIN) AF: 0.000196 AC: 10 AN: 51148

Middle Eastern (MID) AF: 0.000566 AC: 3 AN: 5296

European-Non Finnish (NFE) AF: 0.000619 AC: 678 AN: 1096112

Other (OTH) AF: 0.00154 AC: 91 AN: 59224

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152274 Hom.: 3 Cov.: 33 AF XY: 0.00120 AC XY: 89 AN XY: 74456

African (AFR) AF: 0.000168 AC: 7 AN: 41544

American (AMR) AF: 0.000392 AC: 6 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0210 AC: 109 AN: 5190

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.00126

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000699 AC: 6

ExAC AF: 0.00162 AC: 195

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (8)
-	-	5	not provided (5)
-	-	5	Tuberous sclerosis 2 (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (2)
-	-	2	Tuberous sclerosis syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Benign	0.80
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.038
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.6
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.24
Sift	Benign	0.060	T
Sift4G	Benign	0.19	T
Polyphen		0.77	P
Vest4		0.54
MVP		0.78
ClinPred		0.034	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.43
Mutation Taster		=99/1	polymorphism

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: rs1800748; hg19: chr16-2108755; COSMIC: COSV54761039; COSMIC: COSV54761039;