chr16-2088431-C-T

Variant names:

• chr16-2088431-C-T
• rs45517416
• NM_000548.5:c.5260-15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.5260-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,612,742 control chromosomes in the GnomAD database, including 6 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 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: -2.59
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-2088431-C-T is Benign according to our data. Variant chr16-2088431-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00136 (207/152308) while in subpopulation AFR AF = 0.00166 (69/41564). AF 95% confidence interval is 0.00135. There are 0 homozygotes in GnomAd4. There are 96 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 207 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.5260-15C>T		intron	N/A	NP_000539.2
	TSC2	NM_001406663.1		c.5257-15C>T		intron	N/A	NP_001393592.1
	TSC2	NM_001114382.3		c.5191-15C>T		intron	N/A	NP_001107854.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.5260-15C>T		intron	N/A	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.5191-15C>T		intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.5059-15C>T		intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00159 AC: 397 AN: 249970 AF XY: 0.00161

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000695

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00131 AC: 1909 AN: 1460434 Hom.: 6 Cov.: 33 AF XY: 0.00134 AC XY: 974 AN XY: 726514

African (AFR) AF: 0.00167 AC: 56 AN: 33478

American (AMR) AF: 0.00170 AC: 76 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00194 AC: 167 AN: 86258

European-Finnish (FIN) AF: 0.000635 AC: 33 AN: 52000

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.00133 AC: 1478 AN: 1111990

Other (OTH) AF: 0.00137 AC: 83 AN: 60380

GnomAD4 genome AF: 0.00136 AC: 207 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.00129 AC XY: 96 AN XY: 74468

African (AFR) AF: 0.00166 AC: 69 AN: 41564

American (AMR) AF: 0.000915 AC: 14 AN: 15300

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

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

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 68032

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00146

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	4	Tuberous sclerosis 2 (4)
-	-	3	not provided (3)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.080
DANN	Benign	0.58
PhyloP100		-2.6
Mutation Taster		=99/1	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: rs45517416; hg19: chr16-2138432; COSMIC: COSV104573704;