NM_000548.5:c.4942A>G

Variant names:

• chr16-2086824-A-G
• rs749554579
• NM_000548.5:c.4942A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 5P and 12B. PM1 PM5 PP3 BP6_Very_Strong BS2

The NM_000548.5(TSC2):​c.4942A>G​(p.Ile1648Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,456,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I1648L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.05
• Publications: 1 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 -7 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 32 uncertain in NM_000548.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2086825-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 49458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745
• BP6: Variant 16-2086824-A-G is Benign according to our data. Variant chr16-2086824-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 405966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 15 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.4942A>G	p.Ile1648Val	missense	Exon 38 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.4939A>G	p.Ile1647Val	missense	Exon 38 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.4873A>G	p.Ile1625Val	missense	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.4942A>G	p.Ile1648Val	missense	Exon 38 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.4873A>G	p.Ile1625Val	missense	Exon 37 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4741A>G	p.Ile1581Val	missense	Exon 36 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000247 AC: 6 AN: 242516 AF XY: 0.0000228

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1456572 Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11 AN XY: 724302

African (AFR) AF: 0.0000599 AC: 2 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.000152 AC: 13 AN: 85738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5098

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110428

Other (OTH) AF: 0.00 AC: 0 AN: 60130

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	0.13
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.74	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.4	L
PhyloP100		6.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.60	N
REVEL	Pathogenic	0.65
Sift	Benign	0.24	T
Sift4G	Benign	0.70	T
Polyphen		0.41	B
Vest4		0.55
MutPred		0.79		Gain of phosphorylation at Y1650 (P = 0.1259)
MVP		0.69
ClinPred		0.36	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.49
Mutation Taster		=71/29	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: rs749554579; hg19: chr16-2136825;