rs45517331

Variant names:

• chr16-2084437-C-T
• rs45517331
• NM_000548.5:c.4215C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2084437-C-T
• chr16-2084437-C-A
• chr16-2084437-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000548.5(TSC2):​c.4215C>T​(p.Ala1405Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,609,408 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (20 hom., cov: 34)
  • Exomes 𝑓: 0.0043 (268 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: -1.44
• Publications: 5 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=-0.73).
• BP6: Variant 16-2084437-C-T is Benign according to our data. Variant chr16-2084437-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

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.4215C>T	p.Ala1405Ala	synonymous	Exon 34 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.4212C>T	p.Ala1404Ala	synonymous	Exon 34 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.4146C>T	p.Ala1382Ala	synonymous	Exon 33 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.4215C>T	p.Ala1405Ala	synonymous	Exon 34 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.4146C>T	p.Ala1382Ala	synonymous	Exon 33 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4014C>T	p.Ala1338Ala	synonymous	Exon 32 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152208 Hom.: 20 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0664

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00872 AC: 2097 AN: 240584 AF XY: 0.0120

Gnomad AFR exome AF: 0.000266

Gnomad AMR exome AF: 0.000235

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000279

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000250

Gnomad OTH exome AF: 0.00406

GnomAD4 exome AF: 0.00427 AC: 6221 AN: 1457082 Hom.: 268 Cov.: 33 AF XY: 0.00634 AC XY: 4591 AN XY: 724654

African (AFR) AF: 0.000330 AC: 11 AN: 33366

American (AMR) AF: 0.000180 AC: 8 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39470

South Asian (SAS) AF: 0.0673 AC: 5760 AN: 85594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51590

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5760

European-Non Finnish (NFE) AF: 0.000136 AC: 151 AN: 1110616

Other (OTH) AF: 0.00455 AC: 274 AN: 60212

GnomAD4 genome AF: 0.00217 AC: 331 AN: 152326 Hom.: 20 Cov.: 34 AF XY: 0.00337 AC XY: 251 AN XY: 74488

African (AFR) AF: 0.000120 AC: 5 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0654 AC: 316 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000542 Hom.: 2

Bravo AF: 0.000502

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	Tuberous sclerosis 2 (5)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.90
DANN	Benign	0.55
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs45517331; hg19: chr16-2134438; COSMIC: COSV104573683;