16-2088881-G-GCGCACACA

Variant names:

• chr16-2088881-G-GCGCACACA
• rs142285430
• NM_001009944.3:c.*845_*846insTGTGTGCG

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_*846insTGTGTGCG 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 0.040 (205 hom., cov: 0)
  • Exomes 𝑓: 0.014 (21 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-GCGCACACA is Benign according to our data. Variant chr16-2088881-G-GCGCACACA is described in ClinVar as [Benign]. Clinvar id is 1279025.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*845_*846insTGTGTGCG		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*272_*273insGCACACAC		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_*846insTGTGTGCG		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*272_*273insGCACACAC		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 5930 AN: 146468 Hom.: 204 Cov.: 0

Gnomad AFR AF: 0.0912

Gnomad AMI AF: 0.00885

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00752

Gnomad FIN AF: 0.0450

Gnomad MID AF: 0.0161

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0356

GnomAD4 exome AF: 0.0139 AC: 3822 AN: 274468 Hom.: 21 Cov.: 0 AF XY: 0.0135 AC XY: 1952 AN XY: 145068

African (AFR) AF: 0.0686 AC: 491 AN: 7156

American (AMR) AF: 0.0163 AC: 164 AN: 10068

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 140 AN: 8414

East Asian (EAS) AF: 0.00 AC: 0 AN: 18718

South Asian (SAS) AF: 0.00663 AC: 240 AN: 36214

European-Finnish (FIN) AF: 0.0215 AC: 301 AN: 14032

Middle Eastern (MID) AF: 0.0165 AC: 18 AN: 1090

European-Non Finnish (NFE) AF: 0.0137 AC: 2231 AN: 163308

Other (OTH) AF: 0.0153 AC: 237 AN: 15468

GnomAD4 genome AF: 0.0405 AC: 5936 AN: 146572 Hom.: 205 Cov.: 0 AF XY: 0.0406 AC XY: 2908 AN XY: 71682

African (AFR) AF: 0.0911 AC: 3406 AN: 37404

American (AMR) AF: 0.0272 AC: 407 AN: 14944

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 72 AN: 3424

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00753 AC: 36 AN: 4784

European-Finnish (FIN) AF: 0.0450 AC: 464 AN: 10320

Middle Eastern (MID) AF: 0.0139 AC: 4 AN: 288

European-Non Finnish (NFE) AF: 0.0218 AC: 1467 AN: 67348

Other (OTH) AF: 0.0352 AC: 72 AN: 2046

Alfa AF: 0.00783 Hom.: 9

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;