16-2048270-A-G

Position:

• chr16-2048270-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001318832.2(TSC2):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,080,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TSC2 NM_001318832.2 start_lost
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -2.32

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.-30+205A>G		intron_variant		ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.-30+205A>G		intron_variant		5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000278 AC: 3 AN: 1080520 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 544910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000380

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

TSC2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2024

The TSC2 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). When using the canonical transcript NM_000548, this variant is defined as c.-30+205A>G (Pre-Coding). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.94
DANN	Benign	0.50
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.95	T
PROVEAN	Benign	-0.060	N
Sift	Pathogenic	0.0	D
Vest4		0.11
MVP		0.58
ClinPred		0.051	T
GERP RS		-6.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1023464622; hg19: chr16-2098271;