16-2071623-G-A

Variant names:

• chr16-2071623-G-A
• rs759576009
• NM_000548.5:c.1946+7G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000548.5(TSC2):​c.1946+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: TSC2 NM_000548.5 splice_region, intron
• Scores: Splicing: ADA: 0.0002530
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.540
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-2071623-G-A is Benign according to our data. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071623-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 379713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1946+7G>A		splice_region_variant, intron_variant	Intron 18 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1946+7G>A		splice_region_variant, intron_variant	Intron 18 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000561 AC: 14 AN: 249428 AF XY: 0.0000665

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1460896 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 726750

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111960

Other (OTH) AF: 0.0000331 AC: 2 AN: 60380

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74372

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000869

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Benign:3

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

not specified Benign:1

Dec 08, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.8
DANN	Benign	0.41
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.0
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: rs759576009; hg19: chr16-2121624;