NM_000548.5:c.3818C>T

Variant names:

• chr16-2082439-C-T
• rs749367382
• NM_000548.5:c.3818C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000548.5(TSC2):​c.3818C>T​(p.Ala1273Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,460,228 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. A1273T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (1 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 4.41
• 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23134461).
• BP6: Variant 16-2082439-C-T is Benign according to our data. Variant chr16-2082439-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 380401.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000144 (21/1460228) while in subpopulation MID AF = 0.00156 (9/5768). AF 95% confidence interval is 0.000814. There are 1 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 21 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.3818C>T	p.Ala1273Val	missense	Exon 32 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.3815C>T	p.Ala1272Val	missense	Exon 32 of 42	NP_001393592.1
	TSC2	NM_001406665.1		c.3686C>T	p.Ala1229Val	missense	Exon 31 of 41	NP_001393594.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.3818C>T	p.Ala1273Val	missense	Exon 32 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.3814+641C>T		intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.3682+641C>T		intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 250388 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.000654

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460228 Hom.: 1 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726454

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51844

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111958

Other (OTH) AF: 0.0000497 AC: 3 AN: 60362

GnomAD4 genome Cov.: 33

Alfa AF: 0.000305 Hom.: 1

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	-	2	Tuberous sclerosis 2 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.9	M
PhyloP100		4.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.49
Sift	Benign	0.059	T
Sift4G	Benign	0.17	T
Polyphen		0.020	B
Vest4		0.45
MutPred		0.20		Gain of sheet (P = 0.0101)
MVP		0.90
ClinPred		0.30	T
GERP RS		4.3
PromoterAI		-0.28	Neutral
Varity_R		0.10
gMVP		0.42
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs749367382; hg19: chr16-2132440; COSMIC: COSV54775088; COSMIC: COSV54775088;