rs397515223

Variant names:

• chr16-2071810-A-C
• rs397515223
• NM_000548.5:c.1973A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2071810-A-C
• chr16-2071810-A-G
• chr16-2071810-A-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_000548.5(TSC2):​c.1973A>C​(p.Lys658Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000193 in 1,604,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. K658E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9 O:2
• Conservation: PhyloP100: 6.92
• Publications: 7 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2722392).
• BP6: Variant 16-2071810-A-C is Benign according to our data. Variant chr16-2071810-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 65307.
• BS2: High AC in GnomAd4 at 33 AD gene.

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.1973A>C	p.Lys658Thr	missense	Exon 19 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.1973A>C	p.Lys658Thr	missense	Exon 19 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.1973A>C	p.Lys658Thr	missense	Exon 19 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.1973A>C	p.Lys658Thr	missense	Exon 19 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1973A>C	p.Lys658Thr	missense	Exon 19 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1973A>C	p.Lys658Thr	missense	Exon 19 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.000218 AC: 33 AN: 151696 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000280 AC: 64 AN: 228820 AF XY: 0.000271

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000173

Gnomad FIN exome AF: 0.00133

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.000534

GnomAD4 exome AF: 0.000191 AC: 277 AN: 1452320 Hom.: 1 Cov.: 32 AF XY: 0.000204 AC XY: 147 AN XY: 721654

African (AFR) AF: 0.0000600 AC: 2 AN: 33308

American (AMR) AF: 0.000251 AC: 11 AN: 43826

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25846

East Asian (EAS) AF: 0.000229 AC: 9 AN: 39380

South Asian (SAS) AF: 0.000260 AC: 22 AN: 84590

European-Finnish (FIN) AF: 0.00173 AC: 89 AN: 51378

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5686

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1108316

Other (OTH) AF: 0.000217 AC: 13 AN: 59990

GnomAD4 genome AF: 0.000217 AC: 33 AN: 151810 Hom.: 0 Cov.: 33 AF XY: 0.000270 AC XY: 20 AN XY: 74204

African (AFR) AF: 0.0000242 AC: 1 AN: 41346

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5128

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.00142 AC: 15 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67938

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.000591 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000199 AC: 24

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	3	Tuberous sclerosis 2 (3)
-	1	-	Tuberous sclerosis syndrome (2)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.7	L
PhyloP100		6.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.52
MVP		0.81
ClinPred		0.093	T
GERP RS		5.5
Varity_R		0.23
gMVP		0.52
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs397515223; hg19: chr16-2121811;