rs45473598

Positions:

• chr16-2055406-C-G
• chr16-2055406-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000548.5(TSC2):​c.486C>G​(p.Asp162Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. D162D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.667

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02938962).
• BP6: Variant 16-2055406-C-G is Benign according to our data. Variant chr16-2055406-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1743689.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.486C>G	p.Asp162Glu	missense_variant	6/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.486C>G	p.Asp162Glu	missense_variant	6/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 10, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	4.0
DANN	Benign	0.25
DEOGEN2	Benign	0.33	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.65	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.029	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.14	N;.;.;.;N;N;.;.;.;N;.;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.040	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	1.0	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.0020	B;.;.;.;.;B;.;.;B;B;.;.;.;.;.
Vest4		0.28
MutPred		0.36		Loss of stability (P = 0.3208);Loss of stability (P = 0.3208);Loss of stability (P = 0.3208);.;Loss of stability (P = 0.3208);Loss of stability (P = 0.3208);Loss of stability (P = 0.3208);Loss of stability (P = 0.3208);.;Loss of stability (P = 0.3208);Loss of stability (P = 0.3208);Loss of stability (P = 0.3208);Loss of stability (P = 0.3208);Loss of stability (P = 0.3208);.;
MVP		0.78
ClinPred		0.020	T
GERP RS		-9.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.041
gMVP		0.076

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2105407;