chr16-2088397-C-T

Variant names:

• chr16-2088397-C-T
• rs13332221
• NM_000548.5:c.5260-49C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000548.5(TSC2):​c.5260-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,612,040 control chromosomes in the GnomAD database, including 14,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4060 hom., cov: 34)
  • Exomes 𝑓: 0.10 (10085 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -3.24
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-2088397-C-T is Benign according to our data. Variant chr16-2088397-C-T is described in ClinVar as Benign. ClinVar VariationId is 49420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 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.5260-49C>T		intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.5257-49C>T		intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.5191-49C>T		intron	N/A	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.5260-49C>T		intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.5191-49C>T		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.5059-49C>T		intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28065 AN: 151944 Hom.: 4052 Cov.: 34

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.106 AC: 26485 AN: 249040 AF XY: 0.100

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.0838

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.102 AC: 149391 AN: 1459978 Hom.: 10085 Cov.: 34 AF XY: 0.0993 AC XY: 72157 AN XY: 726318

African (AFR) AF: 0.411 AC: 13748 AN: 33474

American (AMR) AF: 0.0910 AC: 4068 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3724 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0306 AC: 2640 AN: 86256

European-Finnish (FIN) AF: 0.112 AC: 5774 AN: 51674

Middle Eastern (MID) AF: 0.188 AC: 1083 AN: 5766

European-Non Finnish (NFE) AF: 0.100 AC: 111341 AN: 1111880

Other (OTH) AF: 0.116 AC: 7009 AN: 60372

GnomAD4 genome AF: 0.185 AC: 28106 AN: 152062 Hom.: 4060 Cov.: 34 AF XY: 0.180 AC XY: 13390 AN XY: 74364

African (AFR) AF: 0.400 AC: 16582 AN: 41408

American (AMR) AF: 0.138 AC: 2109 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3472

East Asian (EAS) AF: 0.000968 AC: 5 AN: 5166

South Asian (SAS) AF: 0.0290 AC: 140 AN: 4828

European-Finnish (FIN) AF: 0.121 AC: 1283 AN: 10604

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6943 AN: 67982

Other (OTH) AF: 0.165 AC: 348 AN: 2106

Alfa AF: 0.167 Hom.: 1101

Bravo AF: 0.199

Asia WGS AF: 0.0350 AC: 124 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Polycystic kidney disease, adult type (1)
-	-	1	Tuberous sclerosis 2 (1)
-	-	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.29
DANN	Benign	0.60
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs13332221; hg19: chr16-2138398; COSMIC: COSV51909738;