rs13332222

Variant names:

• chr16-2088421-C-G
• rs13332222
• NM_000548.5:c.5260-25C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2088421-C-G
• chr16-2088421-C-A
• chr16-2088421-C-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.5260-25C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,612,392 control chromosomes in the GnomAD database, including 17,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (5899 hom., cov: 33)
  • Exomes 𝑓: 0.11 (12090 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.527
• Publications: 10 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=-0.8).
• BP6: Variant 16-2088421-C-G is Benign according to our data. Variant chr16-2088421-C-G is described in ClinVar as Benign. ClinVar VariationId is 49976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.489 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.5260-25C>G		intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.5257-25C>G		intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.5191-25C>G		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.5260-25C>G		intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.5191-25C>G		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.5059-25C>G		intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32400 AN: 151924 Hom.: 5884 Cov.: 33

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.194

GnomAD2 exomes AF: 0.115 AC: 28677 AN: 249588 AF XY: 0.107

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.0902

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.107 AC: 156378 AN: 1460350 Hom.: 12090 Cov.: 34 AF XY: 0.104 AC XY: 75345 AN XY: 726474

African (AFR) AF: 0.509 AC: 17031 AN: 33474

American (AMR) AF: 0.0977 AC: 4371 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3731 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0315 AC: 2718 AN: 86258

European-Finnish (FIN) AF: 0.113 AC: 5851 AN: 51940

Middle Eastern (MID) AF: 0.194 AC: 1119 AN: 5766

European-Non Finnish (NFE) AF: 0.103 AC: 114028 AN: 1111974

Other (OTH) AF: 0.125 AC: 7526 AN: 60380

GnomAD4 genome AF: 0.214 AC: 32464 AN: 152042 Hom.: 5899 Cov.: 33 AF XY: 0.208 AC XY: 15489 AN XY: 74346

African (AFR) AF: 0.495 AC: 20490 AN: 41400

American (AMR) AF: 0.150 AC: 2298 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3468

East Asian (EAS) AF: 0.000967 AC: 5 AN: 5172

South Asian (SAS) AF: 0.0294 AC: 142 AN: 4834

European-Finnish (FIN) AF: 0.123 AC: 1302 AN: 10602

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7125 AN: 67978

Other (OTH) AF: 0.192 AC: 404 AN: 2106

Alfa AF: 0.0861 Hom.: 166

Bravo AF: 0.231

Asia WGS AF: 0.0450 AC: 159 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	2	Tuberous sclerosis 2 (2)
-	-	1	Polycystic kidney disease, adult type (1)
-	-	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.4
DANN	Benign	0.59
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs13332222; hg19: chr16-2138422; COSMIC: COSV51909741;