16-2062515-C-T

Variant names:

• chr16-2062515-C-T
• rs45478593
• NM_000548.5:c.1276C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001406689.1(TSC2):​c.-69C>T 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 0.00231 in 1,611,650 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (8 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: 0.698
• Publications: 9 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 -16 ACMG points.

• BP6: Variant 16-2062515-C-T is Benign according to our data. Variant chr16-2062515-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49150.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 = 0.00135 (206/152354) while in subpopulation NFE AF = 0.00257 (175/68030). AF 95% confidence interval is 0.00226. There are 1 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 206 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.1276C>T	p.Leu426Leu	synonymous	Exon 13 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406689.1		c.-69C>T		5_prime_UTR_premature_start_codon_gain	Exon 14 of 42	NP_001393618.1
	TSC2	NM_001406690.1		c.-69C>T		5_prime_UTR_premature_start_codon_gain	Exon 14 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.1276C>T	p.Leu426Leu	synonymous	Exon 13 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1276C>T	p.Leu426Leu	synonymous	Exon 13 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1276C>T	p.Leu426Leu	synonymous	Exon 13 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00119 AC: 293 AN: 246194 AF XY: 0.00128

Gnomad AFR exome AF: 0.000385

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000611

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.00241 AC: 3523 AN: 1459296 Hom.: 8 Cov.: 31 AF XY: 0.00234 AC XY: 1697 AN XY: 725594

African (AFR) AF: 0.000269 AC: 9 AN: 33460

American (AMR) AF: 0.000112 AC: 5 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85496

European-Finnish (FIN) AF: 0.000601 AC: 32 AN: 53220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00307 AC: 3407 AN: 1110838

Other (OTH) AF: 0.00111 AC: 67 AN: 60328

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.00125 AC XY: 93 AN XY: 74502

African (AFR) AF: 0.000385 AC: 16 AN: 41590

American (AMR) AF: 0.000588 AC: 9 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00257 AC: 175 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00210 Hom.: 1

Bravo AF: 0.00124

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	4	Tuberous sclerosis 2 (4)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.5
DANN	Benign	0.39
PhyloP100		0.70
PromoterAI		-0.028	Neutral
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45478593; hg19: chr16-2112516; COSMIC: COSV99555949;