16-2071868-C-T

Variant names:

• chr16-2071868-C-T
• rs45517208
• NM_000548.5:c.2031C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000548.5(TSC2):​c.2031C>T​(p.Pro677Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,593,286 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P677P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (36 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25 O:1
• Conservation: PhyloP100: -1.64
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-2071868-C-T is Benign according to our data. Variant chr16-2071868-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 49616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00341 (519/152344) while in subpopulation NFE AF = 0.00637 (433/68022). AF 95% confidence interval is 0.00587. There are 1 homozygotes in GnomAd4. There are 235 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 519 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.2031C>T	p.Pro677Pro	synonymous	Exon 19 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.2031C>T	p.Pro677Pro	synonymous	Exon 19 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.2031C>T	p.Pro677Pro	synonymous	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.2031C>T	p.Pro677Pro	synonymous	Exon 19 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.2031C>T	p.Pro677Pro	synonymous	Exon 19 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.2031C>T	p.Pro677Pro	synonymous	Exon 19 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 519 AN: 152226 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00636

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00255 AC: 534 AN: 209016 AF XY: 0.00254

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000187

Gnomad FIN exome AF: 0.000550

Gnomad NFE exome AF: 0.00494

Gnomad OTH exome AF: 0.00171

GnomAD4 exome AF: 0.00615 AC: 8856 AN: 1440942 Hom.: 36 Cov.: 33 AF XY: 0.00585 AC XY: 4184 AN XY: 715160

African (AFR) AF: 0.00100 AC: 33 AN: 32996

American (AMR) AF: 0.00181 AC: 77 AN: 42490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25704

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38554

South Asian (SAS) AF: 0.000108 AC: 9 AN: 83228

European-Finnish (FIN) AF: 0.000637 AC: 32 AN: 50226

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5686

European-Non Finnish (NFE) AF: 0.00769 AC: 8477 AN: 1102574

Other (OTH) AF: 0.00380 AC: 226 AN: 59484

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152344 Hom.: 1 Cov.: 33 AF XY: 0.00315 AC XY: 235 AN XY: 74500

African (AFR) AF: 0.00123 AC: 51 AN: 41582

American (AMR) AF: 0.00144 AC: 22 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00637 AC: 433 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00415 Hom.: 2

Bravo AF: 0.00317

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	5	not provided (5)
-	-	3	Tuberous sclerosis 2 (3)
-	-	3	Tuberous sclerosis syndrome (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Tuberous sclerosis syndrome;C0349649:Lung lymphangioleiomyomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.40
DANN	Benign	0.60
PhyloP100		-1.6
Mutation Taster		=100/0	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: rs45517208; hg19: chr16-2121869; COSMIC: COSV104587081;