16-2088872-TGCGCGCGC-TGCGCGCGCGCGCGC

Variant names:

• chr16-2088872-T-TGCGCGC
• rs561630495
• NM_001009944.3:c.*849_*854dupGCGCGC

Variant summary

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

The NM_001009944.3(PKD1):​c.*849_*854dupGCGCGC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 500,402 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 0.000028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.04
• 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.*849_*854dupGCGCGC		3_prime_UTR	Exon 46 of 46	NP_001009944.3	P98161-1
	TSC2	NM_000548.5	MANE Select	c.*267_*272dupGCGCGC		3_prime_UTR	Exon 42 of 42	NP_000539.2	P49815-1
	PKD1	NM_000296.4		c.*849_*854dupGCGCGC		3_prime_UTR	Exon 46 of 46	NP_000287.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.*849_*854dupGCGCGC		3_prime_UTR	Exon 46 of 46	ENSP00000262304.4	P98161-1
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.*267_*272dupGCGCGC		3_prime_UTR	Exon 42 of 42	ENSP00000219476.3	P49815-1
	PKD1	ENST00000423118.5	TSL:1	c.*849_*854dupGCGCGC		3_prime_UTR	Exon 46 of 46	ENSP00000399501.1	P98161-3

Frequencies

GnomAD3 genomes AF: 0.0000280 AC: 4 AN: 142866 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000785

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000201

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: 0.0000392 AC: 14 AN: 357536 Hom.: 0 Cov.: 0 AF XY: 0.0000478 AC XY: 9 AN XY: 188286

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

African (AFR) AF: 0.000320 AC: 3 AN: 9366

American (AMR) AF: 0.00 AC: 0 AN: 14430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11066

East Asian (EAS) AF: 0.0000408 AC: 1 AN: 24482

South Asian (SAS) AF: 0.00 AC: 0 AN: 43160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1502

European-Non Finnish (NFE) AF: 0.0000471 AC: 10 AN: 212488

Other (OTH) AF: 0.00 AC: 0 AN: 20494

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000572503), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000280 AC: 4 AN: 142866 Hom.: 0 Cov.: 33 AF XY: 0.0000286 AC XY: 2 AN XY: 69828

African (AFR) AF: 0.0000785 AC: 3 AN: 38232

American (AMR) AF: 0.00 AC: 0 AN: 14210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3290

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4966

South Asian (SAS) AF: 0.00 AC: 0 AN: 4630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64478

Other (OTH) AF: 0.00 AC: 0 AN: 1956

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-6.0

Splicing

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

Other links and lift over

dbSNP: rs561630495; hg19: chr16-2138873;