chr16-2086824-A-G

Position:

• chr16-2086824-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 5P and 12B. PM1 PM5 PP3 BP6_Very_Strong BS2

The NM_000548.5(TSC2):​c.4942A>G​(p.Ile1648Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,456,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1648F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.05

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 Benign. Variant got -7 ACMG points.

• PM1: In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 284 pathogenic changes around while only 47 benign (86%) in NM_000548.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2086824-A-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745
• BP6: Variant 16-2086824-A-G is Benign according to our data. Variant chr16-2086824-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 405966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4942A>G	p.Ile1648Val	missense_variant	38/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4942A>G	p.Ile1648Val	missense_variant	38/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000247 AC: 6 AN: 242516 Hom.: 0 AF XY: 0.0000228 AC XY: 3 AN XY: 131498

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: 0.000201

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1456572 Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11 AN XY: 724302

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 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	0.094
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Benign	0.13
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.74	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.60	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Pathogenic	0.65
Sift	Benign	0.24	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.70	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.41	B;.;.;.;B;B;.;.;P;B;.;.;.;.;.
Vest4		0.55
MutPred		0.79		Gain of phosphorylation at Y1650 (P = 0.1259);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.69
ClinPred		0.36	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.49

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: rs749554579; hg19: chr16-2136825;