16-2088881-GCACA-G

Variant names:

• chr16-2088881-GCACA-G
• rs56279647
• NM_001009944.3:c.*842_*845delTGTG

Variant summary

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

The NM_001009944.3(PKD1):​c.*842_*845delTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0613 in 420,996 control chromosomes in the GnomAD database, including 950 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.056 (279 hom., cov: 0)
  • Exomes 𝑓: 0.064 (671 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-GCACA-G is Benign according to our data. Variant chr16-2088881-GCACA-G is described in ClinVar as [Benign]. Clinvar id is 1271867.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.073 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*842_*845delTGTG		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*286_*289delCACA		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.*842_*845delTGTG		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*286_*289delCACA		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0560 AC: 8214 AN: 146596 Hom.: 279 Cov.: 0

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.0144

Gnomad AMR AF: 0.0459

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.00176

Gnomad SAS AF: 0.0580

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0387

Gnomad NFE AF: 0.0747

Gnomad OTH AF: 0.0484

GnomAD4 exome AF: 0.0641 AC: 17579 AN: 274296 Hom.: 671 AF XY: 0.0626 AC XY: 9072 AN XY: 144970

African (AFR) AF: 0.0176 AC: 127 AN: 7196

American (AMR) AF: 0.0342 AC: 344 AN: 10070

Ashkenazi Jewish (ASJ) AF: 0.0897 AC: 754 AN: 8406

East Asian (EAS) AF: 0.00107 AC: 20 AN: 18706

South Asian (SAS) AF: 0.0547 AC: 1980 AN: 36174

European-Finnish (FIN) AF: 0.0993 AC: 1393 AN: 14022

Middle Eastern (MID) AF: 0.0505 AC: 55 AN: 1090

European-Non Finnish (NFE) AF: 0.0729 AC: 11888 AN: 163176

Other (OTH) AF: 0.0659 AC: 1018 AN: 15456

GnomAD4 genome AF: 0.0560 AC: 8216 AN: 146700 Hom.: 279 Cov.: 0 AF XY: 0.0572 AC XY: 4107 AN XY: 71752

African (AFR) AF: 0.0177 AC: 663 AN: 37480

American (AMR) AF: 0.0459 AC: 687 AN: 14952

Ashkenazi Jewish (ASJ) AF: 0.0818 AC: 280 AN: 3424

East Asian (EAS) AF: 0.00176 AC: 9 AN: 5112

South Asian (SAS) AF: 0.0579 AC: 277 AN: 4786

European-Finnish (FIN) AF: 0.111 AC: 1145 AN: 10342

Middle Eastern (MID) AF: 0.0313 AC: 9 AN: 288

European-Non Finnish (NFE) AF: 0.0747 AC: 5035 AN: 67366

Other (OTH) AF: 0.0479 AC: 98 AN: 2046

Alfa AF: 0.0269 Hom.: 14

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 12, 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

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: rs56279647; hg19: chr16-2138882;