16-2088242-C-A

Variant names:

• chr16-2088242-C-A
• rs761618860
• NM_000548.5:c.5176C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_000548.5(TSC2):​c.5176C>A​(p.His1726Asn) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1726Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77
• Publications: 6 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 50 uncertain in NM_000548.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.5176C>A	p.His1726Asn	missense	Exon 41 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.5173C>A	p.His1725Asn	missense	Exon 41 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.5107C>A	p.His1703Asn	missense	Exon 40 of 41	NP_001107854.1	P49815-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.5176C>A	p.His1726Asn	missense	Exon 41 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.5107C>A	p.His1703Asn	missense	Exon 40 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4975C>A	p.His1659Asn	missense	Exon 39 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.000121 AC: 17 AN: 140432 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000218

Gnomad SAS AF: 0.000220

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000471

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1458884 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 725736

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39098

South Asian (SAS) AF: 0.00 AC: 0 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111208

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000121 AC: 17 AN: 140556 Hom.: 0 Cov.: 33 AF XY: 0.000174 AC XY: 12 AN XY: 68866

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

African (AFR) AF: 0.000323 AC: 12 AN: 37198

American (AMR) AF: 0.00 AC: 0 AN: 14314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3250

East Asian (EAS) AF: 0.000218 AC: 1 AN: 4582

South Asian (SAS) AF: 0.000220 AC: 1 AN: 4548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.0000471 AC: 3 AN: 63660

Other (OTH) AF: 0.00 AC: 0 AN: 1928

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.3	L
PhyloP100		7.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.80
Sift	Benign	0.22	T
Sift4G	Benign	0.085	T
Polyphen		0.99	D
Vest4		0.79
MutPred		0.69		Loss of disorder (P = 0.1429)
MVP		0.79
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.66
gMVP		0.68
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs761618860; hg19: chr16-2138243; COSMIC: COSV51913825;