rs144712953

Variant names:

• chr16-2053685-T-C
• rs144712953
• NM_000548.5:c.336+233T>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000548.5(TSC2):​c.336+233T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 655,444 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (9 hom., cov: 33)
  • Exomes 𝑓: 0.011 (61 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.427

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-2053685-T-C is Benign according to our data. Variant chr16-2053685-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 133428.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.01 (1524/152328) while in subpopulation NFE AF= 0.014 (954/68018). AF 95% confidence interval is 0.0133. There are 9 homozygotes in gnomad4. There are 777 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1524 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.336+233T>C		intron_variant	Intron 4 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.336+233T>C		intron_variant	Intron 4 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1523 AN: 152210 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0351

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00795 AC: 1023 AN: 128756 Hom.: 11 AF XY: 0.00785 AC XY: 553 AN XY: 70430

Gnomad AFR exome AF: 0.00229

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.00321

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0109 AC: 5459 AN: 503116 Hom.: 61 Cov.: 2 AF XY: 0.0102 AC XY: 2789 AN XY: 272878

Gnomad4 AFR exome AF: 0.00295

Gnomad4 AMR exome AF: 0.00568

Gnomad4 ASJ exome AF: 0.00299

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00190

Gnomad4 FIN exome AF: 0.0324

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.0100 AC: 1524 AN: 152328 Hom.: 9 Cov.: 33 AF XY: 0.0104 AC XY: 777 AN XY: 74486

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0351

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0110 Hom.: 1

Bravo AF: 0.00767

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 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. -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.5
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs144712953; hg19: chr16-2103686;