NM_000548.5:c.2074G>A

Variant names:

• chr16-2071911-G-A
• rs201769220
• NM_000548.5:c.2074G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP6 BS2

The NM_000548.5(TSC2):​c.2074G>A​(p.Val692Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000139 in 1,440,556 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. V692L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 6.23
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 32 uncertain in NM_000548.5
• BP6: Variant 16-2071911-G-A is Benign according to our data. Variant chr16-2071911-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226045.
• BS2: High AC in GnomAdExome4 at 20 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.2074G>A	p.Val692Ile	missense	Exon 19 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.2074G>A	p.Val692Ile	missense	Exon 19 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.2074G>A	p.Val692Ile	missense	Exon 19 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.2074G>A	p.Val692Ile	missense	Exon 19 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.2074G>A	p.Val692Ile	missense	Exon 19 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.2074G>A	p.Val692Ile	missense	Exon 19 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000191 AC: 4 AN: 209354 AF XY: 0.00000874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000319

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.0000624

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 20 AN: 1440556 Hom.: 0 Cov.: 33 AF XY: 0.0000154 AC XY: 11 AN XY: 714686

African (AFR) AF: 0.0000604 AC: 2 AN: 33096

American (AMR) AF: 0.0000472 AC: 2 AN: 42398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25642

East Asian (EAS) AF: 0.00 AC: 0 AN: 38718

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83320

European-Finnish (FIN) AF: 0.0000595 AC: 3 AN: 50388

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5622

European-Non Finnish (NFE) AF: 0.00000817 AC: 9 AN: 1101944

Other (OTH) AF: 0.0000337 AC: 2 AN: 59428

GnomAD4 genome Cov.: 33

Alfa AF: 0.000422 Hom.: 1

ExAC AF: 0.0000250 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0042	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.8	L
PhyloP100		6.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.59
Sift	Benign	0.046	D
Sift4G	Benign	0.068	T
Polyphen		0.99	D
Vest4		0.48
MutPred		0.64		Loss of catalytic residue at V692 (P = 0.011)
MVP		0.70
ClinPred		0.21	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.37
Mutation Taster		=89/11	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: rs201769220; hg19: chr16-2121912;