16-2088268-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

The NM_000548.5(TSC2):c.5202T>G(p.Asp1734Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000196 in 1,584,920 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1734N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.915

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 360 pathogenic changes around while only 144 benign (71%) in NM_000548.5
• BS2: High AC in GnomAd at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.5202T>G	p.Asp1734Glu	missense_variant	41/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.5202T>G	p.Asp1734Glu	missense_variant	41/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.000221 AC: 29 AN: 131236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000230

Gnomad ASJ AF: 0.000339

Gnomad EAS AF: 0.000558

Gnomad SAS AF: 0.000503

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000195

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453556 Hom.: 0 Cov.: 36 AF XY: 0.00000277 AC XY: 2 AN XY: 722996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000542

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000221 AC: 29 AN: 131364 Hom.: 0 Cov.: 32 AF XY: 0.000233 AC XY: 15 AN XY: 64356

Gnomad4 AFR AF: 0.000253

Gnomad4 AMR AF: 0.000230

Gnomad4 ASJ AF: 0.000339

Gnomad4 EAS AF: 0.000559

Gnomad4 SAS AF: 0.000502

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000195

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Benign	-0.0079
Eigen_PC	Benign	-0.062
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	0.74	N;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.000046	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.020	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Benign	0.17	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.43
MutPred		0.35		Loss of MoRF binding (P = 0.1222);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.92
ClinPred		0.89	D
GERP RS		3.2
Varity_R		0.33
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1748; hg19: chr16-2138269;