chr16-2071911-G-A

Position:

• chr16-2071911-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000548.5(TSC2):​c.2074G>A​(p.Val692Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000139 in 1,440,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 6.23

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 -5 ACMG points.

• BP6: Variant 16-2071911-G-A is Benign according to our data. Variant chr16-2071911-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226045.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2074G>A	p.Val692Ile	missense_variant	19/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2074G>A	p.Val692Ile	missense_variant	19/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000191 AC: 4 AN: 209354 Hom.: 0 AF XY: 0.00000874 AC XY: 1 AN XY: 114482

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000319

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.0000624

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 20 AN: 1440556 Hom.: 0 Cov.: 33 AF XY: 0.0000154 AC XY: 11 AN XY: 714686

Gnomad4 AFR exome AF: 0.0000604

Gnomad4 AMR exome AF: 0.0000472

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.0000595

Gnomad4 NFE exome AF: 0.00000817

Gnomad4 OTH exome AF: 0.0000337

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000612 Hom.: 0

ExAC AF: 0.0000250 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Tuberous sclerosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Mar 11, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2021

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2020

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	0.12
BayesDel_addAF	Benign	-0.0042	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.8	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.50	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.59
Sift	Benign	0.046	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Benign	0.068	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.99	D;.;.;.;D;D;.;.;P;D;.;.;.;.;.
Vest4		0.48
MutPred		0.64		Loss of catalytic residue at V692 (P = 0.011);Loss of catalytic residue at V692 (P = 0.011);Loss of catalytic residue at V692 (P = 0.011);.;Loss of catalytic residue at V692 (P = 0.011);Loss of catalytic residue at V692 (P = 0.011);Loss of catalytic residue at V692 (P = 0.011);Loss of catalytic residue at V692 (P = 0.011);.;Loss of catalytic residue at V692 (P = 0.011);Loss of catalytic residue at V692 (P = 0.011);Loss of catalytic residue at V692 (P = 0.011);Loss of catalytic residue at V692 (P = 0.011);Loss of catalytic residue at V692 (P = 0.011);.;
MVP		0.70
ClinPred		0.21	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.37

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: rs201769220; hg19: chr16-2121912;