NM_000548.5:c.2348C>G

Variant names:

• chr16-2072976-C-G
• rs562945619
• NM_000548.5:c.2348C>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.2348C>G​(p.Thr783Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,613,518 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. T783I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00040 (10 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.09
• Publications: 5 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 12 benign, 41 uncertain in NM_000548.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0054888725).
• BP6: Variant 16-2072976-C-G is Benign according to our data. Variant chr16-2072976-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 207728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000217 (33/152388) while in subpopulation SAS AF = 0.006 (29/4830). AF 95% confidence interval is 0.00429. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 33 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.2348C>G	p.Thr783Ser	missense	Exon 21 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.2348C>G	p.Thr783Ser	missense	Exon 21 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.2348C>G	p.Thr783Ser	missense	Exon 21 of 41	NP_001107854.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.2348C>G	p.Thr783Ser	missense	Exon 21 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.2348C>G	p.Thr783Ser	missense	Exon 21 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.2348C>G	p.Thr783Ser	missense	Exon 21 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152270 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000833 AC: 209 AN: 250778 AF XY: 0.00117

Gnomad AFR exome AF: 0.000123

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: 0.00000883

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000404 AC: 590 AN: 1461130 Hom.: 10 Cov.: 32 AF XY: 0.000632 AC XY: 459 AN XY: 726838

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00665 AC: 574 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111994

Other (OTH) AF: 0.000166 AC: 10 AN: 60384

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152388 Hom.: 0 Cov.: 33 AF XY: 0.000335 AC XY: 25 AN XY: 74524

African (AFR) AF: 0.0000962 AC: 4 AN: 41592

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00600 AC: 29 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000947 AC: 115

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Tuberous sclerosis 2 (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	TSC2-related disorder (1)
-	-	1	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Benign	0.20
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.63	N
PhyloP100		2.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.24
Sift	Benign	0.74	T
Sift4G	Benign	0.94	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.33		Gain of disorder (P = 0.0371)
MVP		0.71
ClinPred		0.0087	T
GERP RS		3.6
Varity_R		0.043
gMVP		0.092
Mutation Taster		=99/1	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: rs562945619; hg19: chr16-2122977; COSMIC: COSV105872514;