16-2087923-T-G

Position:

• chr16-2087923-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000548.5(TSC2):​c.5050T>G​(p.Ser1684Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in Lovd as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1684P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 284 pathogenic changes around while only 47 benign (86%) in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2087923-T-C is described in Lovd as [Pathogenic].
• PP5: Variant 16-2087923-T-G is Pathogenic according to our data. Variant chr16-2087923-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.5050T>G	p.Ser1684Ala	missense_variant	39/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.5050T>G	p.Ser1684Ala	missense_variant	39/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.086	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.98	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.023	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.0090	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.023	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.52
MutPred		0.63		Loss of catalytic residue at S1684 (P = 0.0646);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.91
ClinPred		0.66	D
GERP RS		1.9
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.37
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs45517387; hg19: chr16-2137924;