NM_000548.5:c.4316G>A

Variant names:

• chr16-2084538-G-A
• rs150397923
• NM_000548.5:c.4316G>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.4316G>A​(p.Gly1439Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000834 in 1,609,116 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. G1439S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (9 hom., cov: 34)
  • Exomes 𝑓: 0.00047 (6 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:2
• Conservation: PhyloP100: 2.90
• Publications: 15 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, 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=0.0051838458).
• BP6: Variant 16-2084538-G-A is Benign according to our data. Variant chr16-2084538-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 65126.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 = 0.00432 (659/152372) while in subpopulation AFR AF = 0.0151 (630/41588). AF 95% confidence interval is 0.0142. There are 9 homozygotes in GnomAd4. There are 303 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 659 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.4316G>A	p.Gly1439Asp	missense	Exon 34 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.4313G>A	p.Gly1438Asp	missense	Exon 34 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.4247G>A	p.Gly1416Asp	missense	Exon 33 of 41	NP_001107854.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.4316G>A	p.Gly1439Asp	missense	Exon 34 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.4247G>A	p.Gly1416Asp	missense	Exon 33 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.4115G>A	p.Gly1372Asp	missense	Exon 32 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 659 AN: 152254 Hom.: 9 Cov.: 34

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.00525

GnomAD2 exomes AF: 0.00116 AC: 275 AN: 238078 AF XY: 0.000811

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.000707

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000469 AC: 683 AN: 1456744 Hom.: 6 Cov.: 33 AF XY: 0.000379 AC XY: 275 AN XY: 724764

African (AFR) AF: 0.0178 AC: 595 AN: 33458

American (AMR) AF: 0.000787 AC: 35 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111236

Other (OTH) AF: 0.000763 AC: 46 AN: 60270

GnomAD4 genome AF: 0.00432 AC: 659 AN: 152372 Hom.: 9 Cov.: 34 AF XY: 0.00407 AC XY: 303 AN XY: 74506

African (AFR) AF: 0.0151 AC: 630 AN: 41588

American (AMR) AF: 0.000914 AC: 14 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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: 68034

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.000997 Hom.: 5

Bravo AF: 0.00484

ESP6500AA AF: 0.0129 AC: 56

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00143 AC: 172

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	4	Tuberous sclerosis 2 (4)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	16
DANN	Benign	0.58
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.53
Sift	Benign	0.63	T
Sift4G	Benign	0.21	T
Polyphen		0.18	B
Vest4		0.30
MVP		0.95
ClinPred		0.018	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.054
gMVP		0.33
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150397923; hg19: chr16-2134539; COSMIC: COSV104375892; COSMIC: COSV104375892;