rs1800725

Variant names:

• chr16-2060794-G-A
• rs1800725
• NM_000548.5:c.1100G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2060794-G-A
• chr16-2060794-G-C
• chr16-2060794-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.1100G>A​(p.Arg367Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0161 in 1,613,742 control chromosomes in the GnomAD database, including 287 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R367W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (28 hom., cov: 32)
  • Exomes 𝑓: 0.017 (259 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:28 O:2
• Conservation: PhyloP100: 6.75
• Publications: 35 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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 32 uncertain in NM_000548.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.007699907).
• BP6: Variant 16-2060794-G-A is Benign according to our data. Variant chr16-2060794-G-A is described in ClinVar as Benign. ClinVar VariationId is 41725.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 = 0.0123 (1874/152190) while in subpopulation NFE AF = 0.0178 (1213/67988). AF 95% confidence interval is 0.017. There are 28 homozygotes in GnomAd4. There are 868 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1874 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.1100G>A	p.Arg367Gln	missense	Exon 11 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.1100G>A	p.Arg367Gln	missense	Exon 11 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.1100G>A	p.Arg367Gln	missense	Exon 11 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.1100G>A	p.Arg367Gln	missense	Exon 11 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1100G>A	p.Arg367Gln	missense	Exon 11 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1100G>A	p.Arg367Gln	missense	Exon 11 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1874 AN: 152074 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0178

Gnomad OTH AF: 0.0173

GnomAD2 exomes AF: 0.0139 AC: 3487 AN: 250570 AF XY: 0.0145

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00749

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0165 AC: 24124 AN: 1461552 Hom.: 259 Cov.: 32 AF XY: 0.0166 AC XY: 12083 AN XY: 727072

African (AFR) AF: 0.00326 AC: 109 AN: 33480

American (AMR) AF: 0.0110 AC: 492 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0292 AC: 762 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.0178 AC: 1533 AN: 86252

European-Finnish (FIN) AF: 0.00773 AC: 411 AN: 53158

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5754

European-Non Finnish (NFE) AF: 0.0176 AC: 19613 AN: 1111976

Other (OTH) AF: 0.0183 AC: 1106 AN: 60386

GnomAD4 genome AF: 0.0123 AC: 1874 AN: 152190 Hom.: 28 Cov.: 32 AF XY: 0.0117 AC XY: 868 AN XY: 74410

African (AFR) AF: 0.00286 AC: 119 AN: 41538

American (AMR) AF: 0.0138 AC: 211 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4820

European-Finnish (FIN) AF: 0.00641 AC: 68 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0178 AC: 1213 AN: 67988

Other (OTH) AF: 0.0171 AC: 36 AN: 2106

Alfa AF: 0.0164 Hom.: 42

Bravo AF: 0.0128

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00500 AC: 22

ESP6500EA AF: 0.0201 AC: 173

ExAC AF: 0.0136 AC: 1653

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0189

EpiControl AF: 0.0185

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (11)
-	-	8	not provided (8)
-	-	5	Tuberous sclerosis 2 (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	Tuberous sclerosis syndrome (3)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0077	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.29
Sift	Benign	0.12	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.59
ClinPred		0.019	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.56
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800725; hg19: chr16-2110795; COSMIC: COSV54769143; COSMIC: COSV54769143;