NM_000548.5:c.101A>G

Variant names:

• chr16-2048716-A-G
• rs777988634
• NM_000548.5:c.101A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000548.5(TSC2):​c.101A>G​(p.Lys34Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. K34T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.32
• Publications: 9 publications found

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]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04574898).
• BP6: Variant 16-2048716-A-G is Benign according to our data. Variant chr16-2048716-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 486619.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.101A>G	p.Lys34Arg	missense_variant	Exon 2 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.101A>G	p.Lys34Arg	missense_variant	Exon 2 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251272 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727166

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000568638), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K34R variant (also known as c.101A>G), located in coding exon 1 of the TSC2 gene, results from an A to G substitution at nucleotide position 101. The lysine at codon 34 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and arginine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tuberous sclerosis 2 Benign:1

Dec 23, 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	0.065
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Uncertain	0.46	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.091	N
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.046	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L;.;.;L;L;.;.;L;L;.;.;L;.;.;.
PhyloP100		1.3
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.3	N;.;.;.;N;.;.;N;N;.;.;.;.;.;N
REVEL	Benign	0.056
Sift	Benign	0.24	T;.;.;.;T;.;.;T;T;.;.;.;.;.;T
Sift4G	Benign	0.38	T;.;.;.;T;.;.;T;T;.;.;.;.;.;T
Polyphen		0.31	B;.;.;.;B;.;.;B;B;.;.;.;.;.;.
Vest4		0.16
MutPred		0.21		Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);Loss of ubiquitination at K34 (P = 0.0067);.;
MVP		0.53
ClinPred		0.070	T
GERP RS		-6.4
PromoterAI		-0.0065	Neutral
Varity_R		0.058
gMVP		0.18
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs777988634; hg19: chr16-2098717;