rs45473698

Variant names:

• chr16-2056724-C-G
• rs45473698
• NM_000548.5:c.729C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2056724-C-G
• chr16-2056724-C-T
• chr16-2056724-C-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_001406689.1(TSC2):​c.-703C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,612,278 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: TSC2 NM_001406689.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21 O:1
• Conservation: PhyloP100: -0.155
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-2056724-C-G is Benign according to our data. Variant chr16-2056724-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49382.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 = 0.00322 (490/152334) while in subpopulation NFE AF = 0.00387 (263/68026). AF 95% confidence interval is 0.00348. There are 1 homozygotes in GnomAd4. There are 276 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 490 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406689.1. 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.729C>G	p.Leu243Leu	synonymous	Exon 8 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406689.1		c.-703C>G		5_prime_UTR_premature_start_codon_gain	Exon 8 of 42	NP_001393618.1
	TSC2	NM_001406690.1		c.-703C>G		5_prime_UTR_premature_start_codon_gain	Exon 8 of 42	NP_001393619.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.729C>G	p.Leu243Leu	synonymous	Exon 8 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.729C>G	p.Leu243Leu	synonymous	Exon 8 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.729C>G	p.Leu243Leu	synonymous	Exon 8 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00322 AC: 490 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00330 AC: 825 AN: 250072 AF XY: 0.00349

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.00354

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00316 AC: 4609 AN: 1459944 Hom.: 9 Cov.: 32 AF XY: 0.00311 AC XY: 2258 AN XY: 726392

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00159 AC: 71 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 104 AN: 26136

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

South Asian (SAS) AF: 0.00226 AC: 195 AN: 86250

European-Finnish (FIN) AF: 0.0117 AC: 605 AN: 51518

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00309 AC: 3433 AN: 1111994

Other (OTH) AF: 0.00310 AC: 187 AN: 60376

GnomAD4 genome AF: 0.00322 AC: 490 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.00370 AC XY: 276 AN XY: 74504

African (AFR) AF: 0.000481 AC: 20 AN: 41570

American (AMR) AF: 0.00150 AC: 23 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4834

European-Finnish (FIN) AF: 0.0139 AC: 148 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00387 AC: 263 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00339 Hom.: 0

Bravo AF: 0.00200

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00379

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	Tuberous sclerosis 2 (5)
-	-	3	not provided (3)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.16
DANN	Benign	0.34
PhyloP100		-0.15
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: rs45473698; hg19: chr16-2106725; COSMIC: COSV104587071;