rs45517203

Variant names:

• chr16-2070558-G-A
• rs45517203
• NM_000548.5:c.1819G>A
• TSC2 p.Ala607Thr

Your query was ambiguous. Multiple possible variants found:

• chr16-2070558-G-A
• chr16-2070558-G-T
• chr16-2070558-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 2P and 18B. PM1 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.1819G>A​(p.Ala607Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00088 in 1,613,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. A607G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00090 (1 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: 6.71
• Publications: 24 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• 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 -16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 39 uncertain in NM_000548.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.21104872).
• BP6: Variant 16-2070558-G-A is Benign according to our data. Variant chr16-2070558-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000669 (102/152360) while in subpopulation NFE AF = 0.00113 (77/68034). AF 95% confidence interval is 0.000928. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 102 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.1819G>A	p.Ala607Thr	missense	Exon 17 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.1819G>A	p.Ala607Thr	missense	Exon 17 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.1819G>A	p.Ala607Thr	missense	Exon 17 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.1819G>A	p.Ala607Thr	missense	Exon 17 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1819G>A	p.Ala607Thr	missense	Exon 17 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1819G>A	p.Ala607Thr	missense	Exon 17 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000655 AC: 164 AN: 250400 AF XY: 0.000641

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000902 AC: 1318 AN: 1460806 Hom.: 1 Cov.: 34 AF XY: 0.000875 AC XY: 636 AN XY: 726708

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00147 AC: 77 AN: 52362

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00105 AC: 1170 AN: 1111996

Other (OTH) AF: 0.000778 AC: 47 AN: 60386

GnomAD4 genome AF: 0.000669 AC: 102 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74506

African (AFR) AF: 0.000433 AC: 18 AN: 41596

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

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: 0.000565 AC: 6 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000893 Hom.: 1

Bravo AF: 0.000533

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	5	Tuberous sclerosis 2 (5)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Tuberous sclerosis syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.8	L
PhyloP100		6.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.55
Sift	Benign	0.15	T
Sift4G	Uncertain	0.012	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.55
Mutation Taster		=79/21	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs45517203; hg19: chr16-2120559; COSMIC: COSV54760167; COSMIC: COSV54760167;