rs45484298

Variant names:

• chr16-2062557-G-A
• rs45484298
• NM_000548.5:c.1318G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2062557-G-A
• chr16-2062557-G-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.1318G>A​(p.Gly440Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,612,336 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. G440V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:23 O:2
• Conservation: PhyloP100: 9.59
• 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: 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=0.05455801).
• BP6: Variant 16-2062557-G-A is Benign according to our data. Variant chr16-2062557-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41726.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0011 (168/152340) while in subpopulation AMR AF = 0.0034 (52/15300). AF 95% confidence interval is 0.00266. There are 0 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 168 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.1318G>A	p.Gly440Ser	missense	Exon 13 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.1318G>A	p.Gly440Ser	missense	Exon 13 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.1318G>A	p.Gly440Ser	missense	Exon 13 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.1318G>A	p.Gly440Ser	missense	Exon 13 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1318G>A	p.Gly440Ser	missense	Exon 13 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1318G>A	p.Gly440Ser	missense	Exon 13 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000693 AC: 171 AN: 246904 AF XY: 0.000696

Gnomad AFR exome AF: 0.000191

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.000606

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.00112 AC: 1631 AN: 1459996 Hom.: 2 Cov.: 31 AF XY: 0.00106 AC XY: 771 AN XY: 726026

African (AFR) AF: 0.000239 AC: 8 AN: 33462

American (AMR) AF: 0.00103 AC: 46 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.000460 AC: 12 AN: 26062

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000584 AC: 5 AN: 85668

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53294

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.00135 AC: 1498 AN: 1111162

Other (OTH) AF: 0.000812 AC: 49 AN: 60350

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.00107 AC XY: 80 AN XY: 74488

African (AFR) AF: 0.000289 AC: 12 AN: 41592

American (AMR) AF: 0.00340 AC: 52 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00113 Hom.: 2

Bravo AF: 0.00106

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000626 AC: 76

EpiCase AF: 0.00180

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	-	5	not specified (6)
-	2	3	Tuberous sclerosis 2 (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Tuberous sclerosis syndrome (3)
-	1	-	Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)
-	-	1	TSC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.7	L
PhyloP100		9.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.24
Sift	Benign	0.091	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.75
MVP		0.91
ClinPred		0.11	T
GERP RS		5.2
PromoterAI		-0.00050	Neutral
Varity_R		0.30
gMVP		0.45
Mutation Taster		=29/71	disease causing

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: rs45484298; hg19: chr16-2112558; COSMIC: COSV108774877; COSMIC: COSV108774877;