rs1376515823

Variant names:

• chr16-2086838-C-G
• rs1376515823
• NM_000548.5:c.4956C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2086838-C-G
• chr16-2086838-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP6_Moderate

The NM_000548.5(TSC2):​c.4956C>G​(p.Asp1652Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. D1652D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.911
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 36 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-2086838-C-G is Benign according to our data. Variant chr16-2086838-C-G is described in ClinVar as Benign. ClinVar VariationId is 3637257.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.4956C>G	p.Asp1652Glu	missense	Exon 38 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.4953C>G	p.Asp1651Glu	missense	Exon 38 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.4887C>G	p.Asp1629Glu	missense	Exon 37 of 41	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.4956C>G	p.Asp1652Glu	missense	Exon 38 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.4887C>G	p.Asp1629Glu	missense	Exon 37 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.4755C>G	p.Asp1585Glu	missense	Exon 36 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000425 AC: 1 AN: 235252 AF XY: 0.00000784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000573

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452966 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722248

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 43874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39266

South Asian (SAS) AF: 0.00 AC: 0 AN: 85168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5142

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108730

Other (OTH) AF: 0.00 AC: 0 AN: 59998

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Benign:1

May 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.28	N
PhyloP100		0.91
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.64
Sift	Benign	0.50	T
Sift4G	Benign	0.49	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.67		Gain of disorder (P = 0.1722)
MVP		0.94
ClinPred		0.39	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.67
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1376515823; hg19: chr16-2136839;