NM_000548.5:c.3883+78G>A

Variant names:

• chr16-2082582-G-A
• rs1800705
• NM_000548.5:c.3883+78G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.3883+78G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0347 in 1,512,880 control chromosomes in the GnomAD database, including 1,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (104 hom., cov: 34)
  • Exomes 𝑓: 0.036 (1007 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.0180
• Publications: 2 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 16-2082582-G-A is Benign according to our data. Variant chr16-2082582-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 49278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0263 (4011/152318) while in subpopulation NFE AF = 0.0403 (2738/68020). AF 95% confidence interval is 0.039. There are 104 homozygotes in GnomAd4. There are 1845 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4011 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.3883+78G>A		intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.3880+78G>A		intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.3814+784G>A		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.3883+78G>A		intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.3814+784G>A		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.3682+784G>A		intron	N/A	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4012 AN: 152200 Hom.: 104 Cov.: 34

Gnomad AFR AF: 0.00709

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0361

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0402

Gnomad OTH AF: 0.0359

GnomAD4 exome AF: 0.0356 AC: 48502 AN: 1360562 Hom.: 1007 Cov.: 23 AF XY: 0.0350 AC XY: 23869 AN XY: 681906

African (AFR) AF: 0.00550 AC: 173 AN: 31460

American (AMR) AF: 0.0224 AC: 996 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 297 AN: 25546

East Asian (EAS) AF: 0.0000765 AC: 3 AN: 39232

South Asian (SAS) AF: 0.0134 AC: 1128 AN: 84416

European-Finnish (FIN) AF: 0.0125 AC: 498 AN: 39788

Middle Eastern (MID) AF: 0.0269 AC: 150 AN: 5582

European-Non Finnish (NFE) AF: 0.0421 AC: 43451 AN: 1032808

Other (OTH) AF: 0.0315 AC: 1806 AN: 57316

GnomAD4 genome AF: 0.0263 AC: 4011 AN: 152318 Hom.: 104 Cov.: 34 AF XY: 0.0248 AC XY: 1845 AN XY: 74480

African (AFR) AF: 0.00707 AC: 294 AN: 41586

American (AMR) AF: 0.0361 AC: 552 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4824

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10622

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0403 AC: 2738 AN: 68020

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

Alfa AF: 0.0371 Hom.: 144

Bravo AF: 0.0276

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	Tuberous sclerosis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.5
DANN	Benign	0.55
PhyloP100		0.018
PromoterAI		0.0038	Neutral
Mutation Taster		=100/0	polymorphism

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: rs1800705; hg19: chr16-2132583; COSMIC: COSV104375803;