rs35282988

Variant names:

• chr16-2086793-G-A
• rs35282988
• NM_000548.5:c.4911G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2086793-G-A
• chr16-2086793-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000548.5(TSC2):​c.4911G>A​(p.Lys1637Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.000652 in 1,611,610 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (4 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15 O:1
• Conservation: PhyloP100: 7.20
• Publications: 6 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 16-2086793-G-A is Benign according to our data. Variant chr16-2086793-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 49331.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000722 (110/152380) while in subpopulation NFE AF = 0.000661 (45/68042). AF 95% confidence interval is 0.000507. There are 1 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 110 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.4911G>A	p.Lys1637Lys	synonymous	Exon 38 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.4908G>A	p.Lys1636Lys	synonymous	Exon 38 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.4842G>A	p.Lys1614Lys	synonymous	Exon 37 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.4911G>A	p.Lys1637Lys	synonymous	Exon 38 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.4842G>A	p.Lys1614Lys	synonymous	Exon 37 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.4710G>A	p.Lys1570Lys	synonymous	Exon 36 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.000722 AC: 110 AN: 152262 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000564

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000884 AC: 220 AN: 248966 AF XY: 0.000851

Gnomad AFR exome AF: 0.000374

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000653

Gnomad NFE exome AF: 0.000598

Gnomad OTH exome AF: 0.000824

GnomAD4 exome AF: 0.000645 AC: 941 AN: 1459230 Hom.: 4 Cov.: 31 AF XY: 0.000632 AC XY: 459 AN XY: 725916

African (AFR) AF: 0.000120 AC: 4 AN: 33430

American (AMR) AF: 0.0000671 AC: 3 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 311 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86172

European-Finnish (FIN) AF: 0.000517 AC: 27 AN: 52222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4848

European-Non Finnish (NFE) AF: 0.000473 AC: 526 AN: 1111802

Other (OTH) AF: 0.00115 AC: 69 AN: 60258

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152380 Hom.: 1 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74510

African (AFR) AF: 0.000264 AC: 11 AN: 41592

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000564 AC: 6 AN: 10632

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

European-Non Finnish (NFE) AF: 0.000661 AC: 45 AN: 68042

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00149 Hom.: 0

Bravo AF: 0.000778

EpiCase AF: 0.000763

EpiControl AF: 0.000949

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	4	Tuberous sclerosis 2 (4)
-	-	3	not provided (3)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.6
DANN	Benign	0.91
PhyloP100		7.2
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs35282988; hg19: chr16-2136794; COSMIC: COSV104375808;