16-2083767-A-T

Variant names:

• chr16-2083767-A-T
• rs45517322
• NM_000548.5:c.3956A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000548.5(TSC2):​c.3956A>T​(p.Asp1319Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,572 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1319N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1 O:1
• Conservation: PhyloP100: 3.71
• 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: 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3956A>T	p.Asp1319Val	missense	Exon 33 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.3953A>T	p.Asp1318Val	missense	Exon 33 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.3887A>T	p.Asp1296Val	missense	Exon 32 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.3956A>T	p.Asp1319Val	missense	Exon 33 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.3887A>T	p.Asp1296Val	missense	Exon 32 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.3755A>T	p.Asp1252Val	missense	Exon 31 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244442 AF XY: 0.00000754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458572 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725340

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 85594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111362

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	1	Tuberous sclerosis 2 (2)
-	1	-	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)
-	-	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.9	L
PhyloP100		3.7
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.88	P
Vest4		0.66
MutPred		0.27		Gain of catalytic residue at D1319 (P = 0.0201)
MVP		0.97
ClinPred		0.89	D
GERP RS		4.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.35
gMVP		0.50
Mutation Taster		=82/18	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: rs45517322; hg19: chr16-2133768;