16-2070522-C-G

Variant names:

• chr16-2070522-C-G
• rs45517199
• NM_000548.5:c.1783C>G

Variant summary

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

The NM_000548.5(TSC2):​c.1783C>G​(p.Gln595Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,461,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 4.09

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=0.2828905).
• BP6: Variant 16-2070522-C-G is Benign according to our data. Variant chr16-2070522-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 406007.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1783C>G	p.Gln595Glu	missense_variant	Exon 17 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1783C>G	p.Gln595Glu	missense_variant	Exon 17 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250758 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1461012 Hom.: 0 Cov.: 34 AF XY: 0.00000826 AC XY: 6 AN XY: 726818

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jan 15, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis 2 Benign:1

Nov 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

May 03, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.079
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Benign	0.45
DEOGEN2	Benign	0.41	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.71	N;.;.;.;N;N;.;.;.;N;.;N;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.29	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.47
Sift	Benign	0.73	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.34	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.95	P;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.48
MutPred		0.51		Gain of ubiquitination at K599 (P = 0.0716);Gain of ubiquitination at K599 (P = 0.0716);Gain of ubiquitination at K599 (P = 0.0716);.;Gain of ubiquitination at K599 (P = 0.0716);Gain of ubiquitination at K599 (P = 0.0716);Gain of ubiquitination at K599 (P = 0.0716);Gain of ubiquitination at K599 (P = 0.0716);.;Gain of ubiquitination at K599 (P = 0.0716);Gain of ubiquitination at K599 (P = 0.0716);Gain of ubiquitination at K599 (P = 0.0716);Gain of ubiquitination at K599 (P = 0.0716);Gain of ubiquitination at K599 (P = 0.0716);.;
MVP		0.78
ClinPred		0.11	T
GERP RS		4.5
Varity_R		0.19
gMVP		0.48

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: rs45517199; hg19: chr16-2120523; COSMIC: COSV54775002; COSMIC: COSV54775002;