chr16-2058741-T-G

Variant names:

• chr16-2058741-T-G
• rs886038358
• NM_000548.5:c.849-6T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000548.5(TSC2):​c.849-6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TSC2 NM_000548.5 splice_region, intron
• Scores: Splicing: ADA: 0.9902
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.02
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-2058741-T-G is Benign according to our data. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638. Variant chr16-2058741-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 256638.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.849-6T>G		splice_region_variant, intron_variant	Intron 9 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.849-6T>G		splice_region_variant, intron_variant	Intron 9 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1 Benign:1

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 9 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 256638). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.54
PhyloP100		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.72
SpliceAI score (max)		0.15		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: rs886038358; hg19: chr16-2108742;