rs137854184

Variant names:

• chr16-2088661-GAAAT-G
• rs137854184
• ENST00000439117.6:n.*4650_*4653delTAAA

Your query was ambiguous. Multiple possible variants found:

• chr16-2088661-GAAAT-G
• chr16-2088661-GAAAT-GAAATAAAT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000439117.6(TSC2):​n.*4650_*4653delTAAA variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,562,330 control chromosomes in the GnomAD database, including 42 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (20 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (22 hom.)
• Consequence: TSC2 ENST00000439117.6 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:2
• Conservation: PhyloP100: -0.631
• 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]

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: ClinGen, Orphanet
• 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 -16 ACMG points.

• BP6: Variant 16-2088661-GAAAT-G is Benign according to our data. Variant chr16-2088661-GAAAT-G is described in ClinVar as Likely_benign. ClinVar VariationId is 49664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00988 (1493/151052) while in subpopulation AFR AF = 0.0323 (1340/41478). AF 95% confidence interval is 0.0309. There are 20 homozygotes in GnomAd4. There are 696 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1493 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000439117.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.*59_*62delTAAA		3_prime_UTR	Exon 42 of 42	NP_000539.2
	TSC2	NR_176225.1		n.5435_5438delTAAA		non_coding_transcript_exon	Exon 40 of 40
	TSC2	NR_176226.1		n.5683_5686delTAAA		non_coding_transcript_exon	Exon 42 of 42

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000439117.6	TSL:1	n.*4650_*4653delTAAA		non_coding_transcript_exon	Exon 38 of 38	ENSP00000406980.2
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.*59_*62delTAAA		3_prime_UTR	Exon 42 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.*59_*62delTAAA		3_prime_UTR	Exon 41 of 41	ENSP00000344383.4

Frequencies

GnomAD3 genomes AF: 0.00989 AC: 1492 AN: 150934 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00388

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00690

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000550

Gnomad OTH AF: 0.00583

GnomAD2 exomes AF: 0.00381 AC: 666 AN: 174634 AF XY: 0.00357

Gnomad AFR exome AF: 0.0313

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00207

Gnomad FIN exome AF: 0.000132

Gnomad NFE exome AF: 0.000570

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.00187 AC: 2633 AN: 1411278 Hom.: 22 AF XY: 0.00192 AC XY: 1344 AN XY: 699972

African (AFR) AF: 0.0350 AC: 1128 AN: 32190

American (AMR) AF: 0.00238 AC: 93 AN: 39076

Ashkenazi Jewish (ASJ) AF: 0.0000391 AC: 1 AN: 25566

East Asian (EAS) AF: 0.00123 AC: 46 AN: 37358

South Asian (SAS) AF: 0.00692 AC: 573 AN: 82830

European-Finnish (FIN) AF: 0.000138 AC: 5 AN: 36288

Middle Eastern (MID) AF: 0.00332 AC: 19 AN: 5722

European-Non Finnish (NFE) AF: 0.000507 AC: 554 AN: 1093348

Other (OTH) AF: 0.00363 AC: 214 AN: 58900

GnomAD4 genome AF: 0.00988 AC: 1493 AN: 151052 Hom.: 20 Cov.: 33 AF XY: 0.00943 AC XY: 696 AN XY: 73790

African (AFR) AF: 0.0323 AC: 1340 AN: 41478

American (AMR) AF: 0.00388 AC: 59 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00213 AC: 11 AN: 5160

South Asian (SAS) AF: 0.00691 AC: 33 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10370

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000550 AC: 37 AN: 67314

Other (OTH) AF: 0.00577 AC: 12 AN: 2080

Alfa AF: 0.000994 Hom.: 0

Bravo AF: 0.0114

Asia WGS AF: 0.00841 AC: 31 AN: 3464

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Tuberous sclerosis syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.63
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: rs137854184; hg19: chr16-2138662; COSMIC: COSV99238248; COSMIC: COSV99238248;