16-2053367-C-T

Variant names:

• chr16-2053367-C-T
• rs35660529
• NM_000548.5:c.251C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000548.5(TSC2):​c.251C>T​(p.Ala84Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000325 in 1,588,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A84T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13 O:2
• Conservation: PhyloP100: 3.07
• Publications: 14 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031080723).
• BP6: Variant 16-2053367-C-T is Benign according to our data. Variant chr16-2053367-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 49212.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000337 (484/1436482) while in subpopulation MID AF = 0.00215 (11/5114). AF 95% confidence interval is 0.00121. There are 0 homozygotes in GnomAdExome4. There are 258 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. 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.251C>T	p.Ala84Val	missense	Exon 4 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.251C>T	p.Ala84Val	missense	Exon 4 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.251C>T	p.Ala84Val	missense	Exon 4 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.251C>T	p.Ala84Val	missense	Exon 4 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.251C>T	p.Ala84Val	missense	Exon 4 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.251C>T	p.Ala84Val	missense	Exon 4 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000322 AC: 67 AN: 208088 AF XY: 0.000410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000132

Gnomad ASJ exome AF: 0.000654

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000394

Gnomad OTH exome AF: 0.000569

GnomAD4 exome AF: 0.000337 AC: 484 AN: 1436482 Hom.: 0 Cov.: 31 AF XY: 0.000362 AC XY: 258 AN XY: 712226

African (AFR) AF: 0.00 AC: 0 AN: 33026

American (AMR) AF: 0.000242 AC: 10 AN: 41300

Ashkenazi Jewish (ASJ) AF: 0.000898 AC: 23 AN: 25612

East Asian (EAS) AF: 0.00 AC: 0 AN: 38496

South Asian (SAS) AF: 0.000816 AC: 67 AN: 82120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50792

Middle Eastern (MID) AF: 0.00215 AC: 11 AN: 5114

European-Non Finnish (NFE) AF: 0.000315 AC: 347 AN: 1100666

Other (OTH) AF: 0.000438 AC: 26 AN: 59356

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74492

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.000196 AC: 3 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

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: 0.000279 AC: 19 AN: 68032

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000325 Hom.: 1

Bravo AF: 0.000212

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000250 AC: 30

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	Tuberous sclerosis 2 (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	1	Tuberous sclerosis syndrome (3)
-	-	1	not specified (1)
-	-	-	Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.79
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.49	N
PhyloP100		3.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.23
Sift	Benign	0.43	T
Sift4G	Benign	0.68	T
Polyphen		0.016	B
Vest4		0.39
MVP		0.54
ClinPred		0.031	T
GERP RS		4.8
PromoterAI		-0.0035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.35
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35660529; hg19: chr16-2103368; COSMIC: COSV107268120;