16-2071869-G-A

Variant names:

• chr16-2071869-G-A
• rs200494044
• NM_000548.5:c.2032G>A

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.2032G>A​(p.Ala678Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000376 in 1,593,938 control chromosomes in the GnomAD database, including 5 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. A678D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (4 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.388
• Publications: 20 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=0.00718987).
• BP6: Variant 16-2071869-G-A is Benign according to our data. Variant chr16-2071869-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 184135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000663 (101/152338) while in subpopulation EAS AF = 0.0128 (66/5174). AF 95% confidence interval is 0.0103. There are 1 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 101 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.2032G>A	p.Ala678Thr	missense	Exon 19 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.2032G>A	p.Ala678Thr	missense	Exon 19 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.2032G>A	p.Ala678Thr	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.2032G>A	p.Ala678Thr	missense	Exon 19 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.2032G>A	p.Ala678Thr	missense	Exon 19 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.2032G>A	p.Ala678Thr	missense	Exon 19 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152220 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00111 AC: 233 AN: 209998 AF XY: 0.00105

Gnomad AFR exome AF: 0.000930

Gnomad AMR exome AF: 0.0000628

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000111

Gnomad OTH exome AF: 0.000758

GnomAD4 exome AF: 0.000345 AC: 498 AN: 1441600 Hom.: 4 Cov.: 33 AF XY: 0.000340 AC XY: 243 AN XY: 715536

African (AFR) AF: 0.000787 AC: 26 AN: 33038

American (AMR) AF: 0.0000705 AC: 3 AN: 42538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25710

East Asian (EAS) AF: 0.00930 AC: 359 AN: 38602

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.0000317 AC: 35 AN: 1102950

Other (OTH) AF: 0.00123 AC: 73 AN: 59502

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152338 Hom.: 1 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74496

African (AFR) AF: 0.000769 AC: 32 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15310

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

East Asian (EAS) AF: 0.0128 AC: 66 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000385 Hom.: 0

Bravo AF: 0.000824

ESP6500AA AF: 0.000481 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000888 AC: 106

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	4	Tuberous sclerosis 2 (4)
-	-	3	Tuberous sclerosis syndrome (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	TSC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	2.2
DANN	Benign	0.40
DEOGEN2	Benign	0.41	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.83	N
PhyloP100		0.39
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.36	N
REVEL	Uncertain	0.48
Sift	Benign	0.46	T
Sift4G	Benign	0.84	T
Polyphen		0.016	B
Vest4		0.21
MVP		0.95
ClinPred		0.0012	T
GERP RS		-0.71
Varity_R		0.027
gMVP		0.30
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: rs200494044; hg19: chr16-2121870;