NM_000548.5:c.1815A>G

Variant names:

• chr16-2070554-A-G
• rs961687056
• NM_000548.5:c.1815A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000548.5(TSC2):​c.1815A>G​(p.Pro605Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,056 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P605P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.439
• Publications: 0 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 16-2070554-A-G is Benign according to our data. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070554-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 382665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.439 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1815A>G	p.Pro605Pro	synonymous_variant	Exon 17 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1815A>G	p.Pro605Pro	synonymous_variant	Exon 17 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250426 AF XY: 0.00000737

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460828 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726714

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

African (AFR) AF: 0.0000482 AC: 2 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Benign:3

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 13, 2016

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. -

Tuberous sclerosis syndrome Benign:1

Mar 09, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Dec 20, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.3
DANN	Benign	0.59
PhyloP100		0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs961687056; hg19: chr16-2120555;