16-2080189-C-T

Variant names:

• chr16-2080189-C-T
• rs34870424
• NM_000548.5:c.3422C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.3422C>T​(p.Ala1141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,612,968 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. A1141T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0055 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (11 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21 O:2
• Conservation: PhyloP100: 2.77
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060076714).
• BP6: Variant 16-2080189-C-T is Benign according to our data. Variant chr16-2080189-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00549 (836/152366) while in subpopulation AFR AF = 0.0193 (804/41590). AF 95% confidence interval is 0.0182. There are 10 homozygotes in GnomAd4. There are 371 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 836 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.3422C>T	p.Ala1141Val	missense	Exon 30 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.3419C>T	p.Ala1140Val	missense	Exon 30 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.3422C>T	p.Ala1141Val	missense	Exon 30 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.3422C>T	p.Ala1141Val	missense	Exon 30 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.3422C>T	p.Ala1141Val	missense	Exon 30 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.3290C>T	p.Ala1097Val	missense	Exon 29 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 835 AN: 152248 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00145 AC: 362 AN: 250372 AF XY: 0.000951

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000564 AC: 824 AN: 1460602 Hom.: 11 Cov.: 32 AF XY: 0.000482 AC XY: 350 AN XY: 726598

African (AFR) AF: 0.0203 AC: 679 AN: 33480

American (AMR) AF: 0.00125 AC: 56 AN: 44724

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: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52186

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111976

Other (OTH) AF: 0.00116 AC: 70 AN: 60378

GnomAD4 genome AF: 0.00549 AC: 836 AN: 152366 Hom.: 10 Cov.: 33 AF XY: 0.00498 AC XY: 371 AN XY: 74502

African (AFR) AF: 0.0193 AC: 804 AN: 41590

American (AMR) AF: 0.00163 AC: 25 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00196 Hom.: 3

Bravo AF: 0.00631

ESP6500AA AF: 0.0189 AC: 83

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00180 AC: 219

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
-	-	4	not provided (4)
-	-	4	Tuberous sclerosis 2 (4)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.50
Sift	Benign	0.34	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.42
MVP		0.95
ClinPred		0.0037	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.017
gMVP		0.27
Mutation Taster		=100/0	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: rs34870424; hg19: chr16-2130190; COSMIC: COSV54760112;