rs370426490

Variant names:

• chr16-2086383-C-A
• rs370426490
• NM_000548.5:c.4849+4C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2086383-C-A
• chr16-2086383-C-G
• chr16-2086383-C-T

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.4849+4C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: TSC2 NM_000548.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001899
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -4.12
• 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: 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=-0.82).
• BP6: Variant 16-2086383-C-A is Benign according to our data. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111. Variant chr16-2086383-C-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 406111.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4849+4C>A		splice_region_variant, intron_variant	Intron 37 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4849+4C>A		splice_region_variant, intron_variant	Intron 37 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1 Benign:1

Jun 05, 2025

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Aug 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 37 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. It affects a nucleotide within the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 406111). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0020
DANN	Benign	0.57
PhyloP100		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.014
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: rs370426490; hg19: chr16-2136384;