rs754556513

Variant names:

• chr16-2071864-G-C
• rs754556513
• NM_000548.5:c.2027G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2071864-G-C
• chr16-2071864-G-T
• chr16-2071864-G-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BP6_Moderate

The NM_000548.5(TSC2):​c.2027G>C​(p.Gly676Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. G676V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10
• Publications: 3 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35374612).
• BP6: Variant 16-2071864-G-C is Benign according to our data. Variant chr16-2071864-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 803149.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2027G>C	p.Gly676Ala	missense	Exon 19 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.2027G>C	p.Gly676Ala	missense	Exon 19 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.2027G>C	p.Gly676Ala	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.2027G>C	p.Gly676Ala	missense	Exon 19 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.2027G>C	p.Gly676Ala	missense	Exon 19 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.2027G>C	p.Gly676Ala	missense	Exon 19 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00000713 AC: 1 AN: 140168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000300

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00422 AC: 431 AN: 102112 AF XY: 0.00333

Gnomad AFR exome AF: 0.00360

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.00420

Gnomad EAS exome AF: 0.00357

Gnomad FIN exome AF: 0.000136

Gnomad NFE exome AF: 0.00242

Gnomad OTH exome AF: 0.00458

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000607 AC: 805 AN: 1326760 Hom.: 0 Cov.: 33 AF XY: 0.000572 AC XY: 372 AN XY: 650638

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

African (AFR) AF: 0.00211 AC: 62 AN: 29422

American (AMR) AF: 0.00955 AC: 280 AN: 29326

Ashkenazi Jewish (ASJ) AF: 0.00137 AC: 29 AN: 21242

East Asian (EAS) AF: 0.0000566 AC: 2 AN: 35362

South Asian (SAS) AF: 0.00170 AC: 109 AN: 64106

European-Finnish (FIN) AF: 0.000809 AC: 32 AN: 39568

Middle Eastern (MID) AF: 0.000785 AC: 3 AN: 3822

European-Non Finnish (NFE) AF: 0.000226 AC: 237 AN: 1049012

Other (OTH) AF: 0.000929 AC: 51 AN: 54900

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000713 AC: 1 AN: 140168 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 67634

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

African (AFR) AF: 0.00 AC: 0 AN: 36732

American (AMR) AF: 0.00 AC: 0 AN: 14066

Ashkenazi Jewish (ASJ) AF: 0.000300 AC: 1 AN: 3332

East Asian (EAS) AF: 0.00 AC: 0 AN: 4824

South Asian (SAS) AF: 0.00 AC: 0 AN: 4474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64778

Other (OTH) AF: 0.00 AC: 0 AN: 1936

⚠️ 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.

Alfa AF: 0.00570 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Benign	0.74
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.66	N
REVEL	Uncertain	0.45
Sift	Benign	0.49	T
Sift4G	Benign	0.45	T
Polyphen		0.17	B
Vest4		0.39
MutPred		0.70		Loss of sheet (P = 0.0084)
MVP		0.93
ClinPred		0.0023	T
GERP RS		4.4
Varity_R		0.040
gMVP		0.41
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754556513; hg19: chr16-2121865; COSMIC: COSV54758705; COSMIC: COSV54758705;