rs1800718

Variant names:

• chr16-2088217-A-C
• rs1800718
• NM_000548.5:c.5161-10A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-2088217-A-C
• chr16-2088217-A-G
• chr16-2088217-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000548.5(TSC2):​c.5161-10A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,612,766 control chromosomes in the GnomAD database, including 45,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (9079 hom., cov: 33)
  • Exomes 𝑓: 0.21 (36010 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Scores: Splicing: ADA: 0.00002236
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20 O:1
• Conservation: PhyloP100: -2.26
• Publications: 15 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-2088217-A-C is Benign according to our data. Variant chr16-2088217-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

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.5161-10A>C		intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.5158-10A>C		intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.5092-10A>C		intron	N/A	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.5161-10A>C		intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.5092-10A>C		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4960-10A>C		intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45467 AN: 151892 Hom.: 9050 Cov.: 33

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0966

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.266

GnomAD2 exomes AF: 0.200 AC: 50039 AN: 250654 AF XY: 0.193

Gnomad AFR exome AF: 0.560

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.209 AC: 305591 AN: 1460756 Hom.: 36010 Cov.: 35 AF XY: 0.205 AC XY: 148942 AN XY: 726648

African (AFR) AF: 0.565 AC: 18905 AN: 33478

American (AMR) AF: 0.139 AC: 6210 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 6637 AN: 26136

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0992 AC: 8555 AN: 86258

European-Finnish (FIN) AF: 0.255 AC: 13375 AN: 52372

Middle Eastern (MID) AF: 0.268 AC: 1543 AN: 5768

European-Non Finnish (NFE) AF: 0.213 AC: 236972 AN: 1111944

Other (OTH) AF: 0.222 AC: 13381 AN: 60378

GnomAD4 genome AF: 0.300 AC: 45546 AN: 152010 Hom.: 9079 Cov.: 33 AF XY: 0.295 AC XY: 21932 AN XY: 74304

African (AFR) AF: 0.559 AC: 23137 AN: 41422

American (AMR) AF: 0.212 AC: 3246 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 845 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5176

South Asian (SAS) AF: 0.0963 AC: 465 AN: 4828

European-Finnish (FIN) AF: 0.260 AC: 2756 AN: 10584

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14316 AN: 67928

Other (OTH) AF: 0.263 AC: 557 AN: 2114

Alfa AF: 0.252 Hom.: 5221

Bravo AF: 0.308

Asia WGS AF: 0.0850 AC: 296 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Tuberous sclerosis 2 (5)
-	-	4	not provided (4)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.072
DANN	Benign	0.34
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0020
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: rs1800718; hg19: chr16-2138218; COSMIC: COSV99237259;