16-2060772-A-G

Variant names:

• chr16-2060772-A-G
• rs1555500560
• NM_000548.5:c.1078A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM2 PM5 BP4_Moderate BP6 BS2

The NM_000548.5(TSC2):​c.1078A>G​(p.Ile360Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict 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. I360?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.03

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2060772-ATT-AA is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.11255753).
• BP6: Variant 16-2060772-A-G is Benign according to our data. Variant chr16-2060772-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 467842.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1078A>G	p.Ile360Val	missense_variant	Exon 11 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1078A>G	p.Ile360Val	missense_variant	Exon 11 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461666 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727130

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Oct 11, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I360V variant (also known as c.1078A>G), located in coding exon 10 of the TSC2 gene, results from an A to G substitution at nucleotide position 1078. The isoleucine at codon 360 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Tuberous sclerosis 2 Benign:1

Sep 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.39	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.0	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.62	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Benign	0.23
Sift	Benign	0.15	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.13	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.88	P;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.43
MutPred		0.41		Gain of MoRF binding (P = 0.1344);Gain of MoRF binding (P = 0.1344);Gain of MoRF binding (P = 0.1344);.;Gain of MoRF binding (P = 0.1344);Gain of MoRF binding (P = 0.1344);Gain of MoRF binding (P = 0.1344);Gain of MoRF binding (P = 0.1344);.;Gain of MoRF binding (P = 0.1344);Gain of MoRF binding (P = 0.1344);Gain of MoRF binding (P = 0.1344);Gain of MoRF binding (P = 0.1344);Gain of MoRF binding (P = 0.1344);.;
MVP		0.57
ClinPred		0.087	T
GERP RS		-0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.079
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555500560; hg19: chr16-2110773;