rs878854121

Variant names:

• chr16-2058819-C-A
• rs878854121
• NM_000548.5:c.921C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2058819-C-A
• chr16-2058819-C-G
• chr16-2058819-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000548.5(TSC2):​c.921C>A​(p.His307Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,450,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H307Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• 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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.921C>A	p.His307Gln	missense_variant	Exon 10 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.921C>A	p.His307Gln	missense_variant	Exon 10 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1450762 Hom.: 0 Cov.: 32 AF XY: 0.00000416 AC XY: 3 AN XY: 720434

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 42942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25812

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 83996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000633 AC: 7 AN: 1106716

Other (OTH) AF: 0.00 AC: 0 AN: 60040

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 307 of the TSC2 protein (p.His307Gln). 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: 2057881). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	0.089
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.6	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
PhyloP100		2.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.016	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.016	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.99	D;.;.;.;D;B;.;.;D;B;.;.;.;.;.
Vest4		0.70
MutPred		0.41		Gain of catalytic residue at H307 (P = 0.0565);Gain of catalytic residue at H307 (P = 0.0565);Gain of catalytic residue at H307 (P = 0.0565);.;Gain of catalytic residue at H307 (P = 0.0565);Gain of catalytic residue at H307 (P = 0.0565);Gain of catalytic residue at H307 (P = 0.0565);Gain of catalytic residue at H307 (P = 0.0565);.;Gain of catalytic residue at H307 (P = 0.0565);Gain of catalytic residue at H307 (P = 0.0565);Gain of catalytic residue at H307 (P = 0.0565);Gain of catalytic residue at H307 (P = 0.0565);Gain of catalytic residue at H307 (P = 0.0565);.;
MVP		0.91
ClinPred		0.92	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.33
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs878854121; hg19: chr16-2108820;