rs1800705

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 49278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2082582-G-A is described in Lovd as [Benign]. Variant chr16-2082582-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4011 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3883+78G>A		intron_variant	Intron 32 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3883+78G>A		intron_variant	Intron 32 of 41	5	NM_000548.5	ENSP00000219476.3

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

Gnomad4 AFR exome AF: 0.00550

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0000765

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0421

Gnomad4 OTH exome AF: 0.0315

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

Gnomad4 AFR AF: 0.00707

Gnomad4 AMR AF: 0.0361

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.0403

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.0304 Hom.: 14

Bravo AF: 0.0276

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 15, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Tuberous sclerosis syndrome Other:1

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Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.5
DANN	Benign	0.55

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

Publications

LitVar

Other links and lift over

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