16-2088881-G-GCGCACA

Variant names:

• chr16-2088881-G-GCGCACA
• rs142285430
• NM_001009944.3:c.*845_*846insTGTGCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001009944.3(PKD1):​c.*845_*846insTGTGCG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (2343 hom., cov: 0)
  • Exomes 𝑓: 0.048 (287 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.365
• Publications: 1 publications found

Genes affected

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]

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 -10 ACMG points.

• BP6: Variant 16-2088881-G-GCGCACA is Benign according to our data. Variant chr16-2088881-G-GCGCACA is described in ClinVar as [Benign]. Clinvar id is 1229544.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*845_*846insTGTGCG		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*272_*273insGCACAC		3_prime_UTR_variant	Exon 42 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.*845_*846insTGTGCG		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*272_*273insGCACAC		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.142 AC: 20739 AN: 146246 Hom.: 2341 Cov.: 0

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.0232

Gnomad FIN AF: 0.0681

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.0746

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.0484 AC: 13239 AN: 273490 Hom.: 287 Cov.: 0 AF XY: 0.0456 AC XY: 6599 AN XY: 144600

African (AFR) AF: 0.224 AC: 1573 AN: 7034

American (AMR) AF: 0.0511 AC: 513 AN: 10034

Ashkenazi Jewish (ASJ) AF: 0.0829 AC: 692 AN: 8344

East Asian (EAS) AF: 0.0000534 AC: 1 AN: 18718

South Asian (SAS) AF: 0.0160 AC: 580 AN: 36176

European-Finnish (FIN) AF: 0.0390 AC: 546 AN: 13988

Middle Eastern (MID) AF: 0.103 AC: 111 AN: 1082

European-Non Finnish (NFE) AF: 0.0507 AC: 8247 AN: 162720

Other (OTH) AF: 0.0634 AC: 976 AN: 15394

GnomAD4 genome AF: 0.142 AC: 20765 AN: 146350 Hom.: 2343 Cov.: 0 AF XY: 0.137 AC XY: 9814 AN XY: 71578

African (AFR) AF: 0.336 AC: 12530 AN: 37262

American (AMR) AF: 0.103 AC: 1532 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 423 AN: 3416

East Asian (EAS) AF: 0.000587 AC: 3 AN: 5112

South Asian (SAS) AF: 0.0230 AC: 110 AN: 4778

European-Finnish (FIN) AF: 0.0681 AC: 702 AN: 10310

Middle Eastern (MID) AF: 0.205 AC: 59 AN: 288

European-Non Finnish (NFE) AF: 0.0747 AC: 5026 AN: 67308

Other (OTH) AF: 0.138 AC: 282 AN: 2046

Alfa AF: 0.0258 Hom.: 9

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142285430; hg19: chr16-2138882; COSMIC: COSV51914339; COSMIC: COSV51914339;