rs35364892

Variant names:

• chr16-2056112-C-T
• rs35364892
• NM_000548.5:c.600-84C>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_001406680.1(TSC2):​c.-85C>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 0.00924 in 1,568,486 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (104 hom.)
• Consequence: TSC2 NM_001406680.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.508
• Publications: 2 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 16-2056112-C-T is Benign according to our data. Variant chr16-2056112-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 49409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0078 (1188/152232) while in subpopulation SAS AF = 0.0187 (90/4822). AF 95% confidence interval is 0.0156. There are 10 homozygotes in GnomAd4. There are 588 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1188 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406680.1. 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.600-84C>T		intron	N/A	NP_000539.2
	TSC2	NM_001406680.1		c.-85C>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 42	NP_001393609.1
	TSC2	NM_001406683.1		c.-85C>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 41	NP_001393612.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.600-84C>T		intron	N/A	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.600-84C>T		intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.600-84C>T		intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.00782 AC: 1189 AN: 152116 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00760

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00717

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00764

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.00911 AC: 2183 AN: 239650 AF XY: 0.0101

Gnomad AFR exome AF: 0.00666

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.0369

Gnomad EAS exome AF: 0.000274

Gnomad FIN exome AF: 0.00611

Gnomad NFE exome AF: 0.00808

Gnomad OTH exome AF: 0.00916

GnomAD4 exome AF: 0.00939 AC: 13299 AN: 1416254 Hom.: 104 Cov.: 26 AF XY: 0.00982 AC XY: 6946 AN XY: 707014

African (AFR) AF: 0.00767 AC: 251 AN: 32708

American (AMR) AF: 0.00342 AC: 152 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.0371 AC: 959 AN: 25878

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39458

South Asian (SAS) AF: 0.0195 AC: 1665 AN: 85232

European-Finnish (FIN) AF: 0.00657 AC: 297 AN: 45218

Middle Eastern (MID) AF: 0.00915 AC: 52 AN: 5680

European-Non Finnish (NFE) AF: 0.00859 AC: 9269 AN: 1078544

Other (OTH) AF: 0.0110 AC: 648 AN: 59052

GnomAD4 genome AF: 0.00780 AC: 1188 AN: 152232 Hom.: 10 Cov.: 32 AF XY: 0.00790 AC XY: 588 AN XY: 74414

African (AFR) AF: 0.00756 AC: 314 AN: 41548

American (AMR) AF: 0.00373 AC: 57 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.0187 AC: 90 AN: 4822

European-Finnish (FIN) AF: 0.00717 AC: 76 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00765 AC: 520 AN: 68014

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.0102 Hom.: 3

Bravo AF: 0.00736

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.52
PhyloP100		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs35364892; hg19: chr16-2106113; COSMIC: COSV54761845;