rs397515306

chr16-2077723-G-Achr16-2077723-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_000548.5(TSC2):c.2963G>A(p.Arg988His) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,612,520 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R988C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.97

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35007113).
• BP6: Variant 16-2077723-G-A is Benign according to our data. Variant chr16-2077723-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 467980.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}. Variant chr16-2077723-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.2963G>A	p.Arg988His	missense_variant	26/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.2963G>A	p.Arg988His	missense_variant	26/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250026 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000459 AC: 67 AN: 1460184 Hom.: 0 Cov.: 31 AF XY: 0.0000372 AC XY: 27 AN XY: 726426

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74490

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 20, 2024	The p.R988H variant (also known as c.2963G>A), located in coding exon 25 of the TSC2 gene, results from a G to A substitution at nucleotide position 2963. The arginine at codon 988 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tuberous sclerosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;.;.;.
Eigen	Benign	-0.0021
Eigen_PC	Benign	0.055
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.2	L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N;.;.;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Uncertain	0.013	D;.;.;D
Polyphen		0.0040	B;.;.;D
Vest4		0.52
MVP		0.87
ClinPred		0.43	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.45

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: rs397515306; hg19: chr16-2127724;