rs1800742

Variant names:

• chr16-2060804-G-A
• rs1800742
• NM_000548.5:c.1110G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2060804-G-A
• chr16-2060804-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000548.5(TSC2):​c.1110G>A​(p.Gln370Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,538 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (9 hom., cov: 33)
  • Exomes 𝑓: 0.011 (113 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:22 O:1
• Conservation: PhyloP100: 2.02
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 16-2060804-G-A is Benign according to our data. Variant chr16-2060804-G-A is described in ClinVar as Benign. ClinVar VariationId is 49141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00814 (1240/152292) while in subpopulation NFE AF = 0.0115 (782/68030). AF 95% confidence interval is 0.0108. There are 9 homozygotes in GnomAd4. There are 581 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1240 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.1110G>A	p.Gln370Gln	synonymous	Exon 11 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.1110G>A	p.Gln370Gln	synonymous	Exon 11 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.1110G>A	p.Gln370Gln	synonymous	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.1110G>A	p.Gln370Gln	synonymous	Exon 11 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1110G>A	p.Gln370Gln	synonymous	Exon 11 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1110G>A	p.Gln370Gln	synonymous	Exon 11 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00817 AC: 1243 AN: 152174 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0100 AC: 2511 AN: 250212 AF XY: 0.0101

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.0335

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00603

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0108 AC: 15849 AN: 1461246 Hom.: 113 Cov.: 32 AF XY: 0.0107 AC XY: 7781 AN XY: 726922

African (AFR) AF: 0.00266 AC: 89 AN: 33478

American (AMR) AF: 0.00537 AC: 240 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0313 AC: 819 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00526 AC: 454 AN: 86240

European-Finnish (FIN) AF: 0.00649 AC: 344 AN: 52982

Middle Eastern (MID) AF: 0.0502 AC: 288 AN: 5740

European-Non Finnish (NFE) AF: 0.0116 AC: 12844 AN: 1111894

Other (OTH) AF: 0.0128 AC: 771 AN: 60376

GnomAD4 genome AF: 0.00814 AC: 1240 AN: 152292 Hom.: 9 Cov.: 33 AF XY: 0.00780 AC XY: 581 AN XY: 74456

African (AFR) AF: 0.00193 AC: 80 AN: 41554

American (AMR) AF: 0.00863 AC: 132 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10616

Middle Eastern (MID) AF: 0.0548 AC: 16 AN: 292

European-Non Finnish (NFE) AF: 0.0115 AC: 782 AN: 68030

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.0108 Hom.: 11

Bravo AF: 0.00851

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0124

EpiControl AF: 0.0133

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	Tuberous sclerosis 2 (5)
-	-	4	not provided (4)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	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
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.8
DANN	Benign	0.59
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1800742; hg19: chr16-2110805; COSMIC: COSV99554856;