16-2088891-AC-A

Variant names:

• chr16-2088891-AC-A
• rs1222652018
• NM_001009944.3:c.*835delG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001009944.3(PKD1):​c.*835delG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00417 in 446,960 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0094 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (8 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.293
• Publications: 0 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 16-2088891-AC-A is Benign according to our data. Variant chr16-2088891-AC-A is described in ClinVar as [Likely_benign]. Clinvar id is 1218692.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00944 (1385/146764) while in subpopulation AFR AF = 0.0344 (1254/36480). AF 95% confidence interval is 0.0328. There are 21 homozygotes in GnomAd4. There are 670 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*835delG		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*282delC		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.*835delG		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*282delC		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00938 AC: 1375 AN: 146648 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00751

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00740

GnomAD4 exome AF: 0.00160 AC: 480 AN: 300196 Hom.: 8 Cov.: 0 AF XY: 0.00147 AC XY: 232 AN XY: 158154

African (AFR) AF: 0.0373 AC: 296 AN: 7940

American (AMR) AF: 0.00244 AC: 27 AN: 11060

Ashkenazi Jewish (ASJ) AF: 0.00719 AC: 69 AN: 9592

East Asian (EAS) AF: 0.00 AC: 0 AN: 20258

South Asian (SAS) AF: 0.0000529 AC: 2 AN: 37782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15422

Middle Eastern (MID) AF: 0.00455 AC: 6 AN: 1320

European-Non Finnish (NFE) AF: 0.000189 AC: 34 AN: 179752

Other (OTH) AF: 0.00269 AC: 46 AN: 17070

GnomAD4 genome AF: 0.00944 AC: 1385 AN: 146764 Hom.: 21 Cov.: 33 AF XY: 0.00932 AC XY: 670 AN XY: 71900

African (AFR) AF: 0.0344 AC: 1254 AN: 36480

American (AMR) AF: 0.00510 AC: 77 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.00751 AC: 26 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67898

Other (OTH) AF: 0.00732 AC: 15 AN: 2050

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Likely 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		-0.29
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: rs1222652018; hg19: chr16-2138892;