16-2058827-A-T

Variant names:

• chr16-2058827-A-T
• rs878854122
• NM_000548.5:c.929A>T
• TSC2 p.Tyr310Phe

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000548.5(TSC2):​c.929A>T​(p.Tyr310Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,605,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y310C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1 O:1
• Conservation: PhyloP100: 1.51
• Publications: 8 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059007198).
• BP6: Variant 16-2058827-A-T is Benign according to our data. Variant chr16-2058827-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 577044.

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.929A>T	p.Tyr310Phe	missense	Exon 10 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.929A>T	p.Tyr310Phe	missense	Exon 10 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.929A>T	p.Tyr310Phe	missense	Exon 10 of 41	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.929A>T	p.Tyr310Phe	missense	Exon 10 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.929A>T	p.Tyr310Phe	missense	Exon 10 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.929A>T	p.Tyr310Phe	missense	Exon 10 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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

GnomAD2 exomes AF: 0.00000424 AC: 1 AN: 235618 AF XY: 0.00000786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453300 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 721930

African (AFR) AF: 0.0000598 AC: 2 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 43452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.00 AC: 0 AN: 84322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108044

Other (OTH) AF: 0.0000166 AC: 1 AN: 60134

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

African (AFR) AF: 0.0000724 AC: 3 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)
-	-	1	Tuberous sclerosis 2 (2)
-	1	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.26
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.28
Sift	Benign	0.68	T
Sift4G	Benign	0.69	T
Varity_R		0.062
gMVP		0.13
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs878854122;

hg19: chr16-2108828;