16-2088879-G-GCACA

Variant names:

• chr16-2088879-G-GCACA
• rs1371941622
• NM_001009944.3:c.*847_*848insTGTG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001009944.3(PKD1):​c.*847_*848insTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 469,712 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.370
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*847_*848insTGTG		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*270_*271insACAC		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.*847_*848insTGTG		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*270_*271insACAC		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.000167 AC: 19 AN: 114046 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000906

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000562 AC: 2 AN: 355596 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 186790

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000198 AC: 2 AN: 10082

American (AMR) AF: 0.00 AC: 0 AN: 14154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11188

East Asian (EAS) AF: 0.00 AC: 0 AN: 24374

South Asian (SAS) AF: 0.00 AC: 0 AN: 42978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1512

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 210646

Other (OTH) AF: 0.00 AC: 0 AN: 20430

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000166 AC: 19 AN: 114116 Hom.: 0 Cov.: 33 AF XY: 0.000125 AC XY: 7 AN XY: 55990

African (AFR) AF: 0.000904 AC: 19 AN: 21026

American (AMR) AF: 0.00 AC: 0 AN: 12008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2818

East Asian (EAS) AF: 0.00 AC: 0 AN: 4934

South Asian (SAS) AF: 0.00 AC: 0 AN: 4426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 222

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57794

Other (OTH) AF: 0.00 AC: 0 AN: 1648

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.37

Splicing

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

Other links and lift over

dbSNP: rs1371941622; hg19: chr16-2138880;