rs45517419

Variant names:

• chr16-2088545-G-A
• rs45517419
• NM_000548.5:c.5359G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2088545-G-A
• chr16-2088545-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000548.5(TSC2):​c.5359G>A​(p.Gly1787Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,612,070 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1787R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (10 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:21 O:2
• Conservation: PhyloP100: 0.0120
• Publications: 23 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]

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007300496).
• BP6: Variant 16-2088545-G-A is Benign according to our data. Variant chr16-2088545-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41746.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00255 (389/152334) while in subpopulation NFE AF = 0.004 (272/68034). AF 95% confidence interval is 0.00361. There are 4 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 389 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.5359G>A	p.Gly1787Ser	missense	Exon 42 of 42	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.5356G>A	p.Gly1786Ser	missense	Exon 42 of 42	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.5290G>A	p.Gly1764Ser	missense	Exon 41 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.5359G>A	p.Gly1787Ser	missense	Exon 42 of 42	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.5290G>A	p.Gly1764Ser	missense	Exon 41 of 41	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.5158G>A	p.Gly1720Ser	missense	Exon 40 of 40	ENSP00000384468.2	P49815-5

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 389 AN: 152218 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00213 AC: 530 AN: 249038 AF XY: 0.00209

Gnomad AFR exome AF: 0.000373

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00545

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00165 AC: 2407 AN: 1459736 Hom.: 10 Cov.: 33 AF XY: 0.00172 AC XY: 1250 AN XY: 726186

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000582 AC: 26 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000696 AC: 60 AN: 86252

European-Finnish (FIN) AF: 0.00605 AC: 311 AN: 51364

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

European-Non Finnish (NFE) AF: 0.00164 AC: 1828 AN: 1111958

Other (OTH) AF: 0.00164 AC: 99 AN: 60374

GnomAD4 genome AF: 0.00255 AC: 389 AN: 152334 Hom.: 4 Cov.: 33 AF XY: 0.00277 AC XY: 206 AN XY: 74482

African (AFR) AF: 0.000192 AC: 8 AN: 41576

American (AMR) AF: 0.00170 AC: 26 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00584 AC: 62 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00400 AC: 272 AN: 68034

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00267 Hom.: 2

Bravo AF: 0.00156

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00251 AC: 304

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00184

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	5	Tuberous sclerosis 2 (5)
-	-	4	Tuberous sclerosis syndrome (5)
-	-	3	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	TSC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	0.31
DANN	Benign	0.50
DEOGEN2	Benign	0.37	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.012
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.53
Sift	Benign	0.71	T
Sift4G	Benign	0.51	T
Polyphen		0.024	B
Vest4		0.14
MVP		0.96
ClinPred		0.00062	T
GERP RS		-0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.39
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: rs45517419; hg19: chr16-2138546; COSMIC: COSV104375928;