16-2088256-C-T

Variant names:

• chr16-2088256-C-T
• rs1305025066
• NM_000548.5:c.5190C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000548.5(TSC2):​c.5190C>T​(p.Ser1730Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,595,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1730S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000073 (0 hom., cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.423
• Publications: 0 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 16-2088256-C-T is Benign according to our data. Variant chr16-2088256-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 825527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.423 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.5190C>T	p.Ser1730Ser	synonymous	Exon 41 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.5187C>T	p.Ser1729Ser	synonymous	Exon 41 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.5121C>T	p.Ser1707Ser	synonymous	Exon 40 of 41	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.5190C>T	p.Ser1730Ser	synonymous	Exon 41 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.5121C>T	p.Ser1707Ser	synonymous	Exon 40 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.4989C>T	p.Ser1663Ser	synonymous	Exon 39 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.00000732 AC: 1 AN: 136644 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000161

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458980 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725790

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 38932

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111400

Other (OTH) AF: 0.00 AC: 0 AN: 60322

GnomAD4 genome AF: 0.00000732 AC: 1 AN: 136644 Hom.: 0 Cov.: 33 AF XY: 0.0000149 AC XY: 1 AN XY: 67014

African (AFR) AF: 0.00 AC: 0 AN: 35712

American (AMR) AF: 0.00 AC: 0 AN: 13804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3172

East Asian (EAS) AF: 0.00 AC: 0 AN: 4560

South Asian (SAS) AF: 0.00 AC: 0 AN: 4354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000161 AC: 1 AN: 62112

Other (OTH) AF: 0.00 AC: 0 AN: 1836

Alfa AF: 0.0000712 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.5
DANN	Benign	0.87
PhyloP100		-0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1305025066; hg19: chr16-2138257; COSMIC: COSV51915543;