16-2088881-GCACACACACACA-GCACACACACACACACACACACACA

Variant names:

• chr16-2088881-G-GCACACACACACA
• rs56279647
• NM_001009944.3:c.*834_*845dupTGTGTGTGTGTG

Variant summary

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

The NM_001009944.3(PKD1):​c.*834_*845dupTGTGTGTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: 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.*834_*845dupTGTGTGTGTGTG		3_prime_UTR	Exon 46 of 46	NP_001009944.3	P98161-1
	TSC2	NM_000548.5	MANE Select	c.*278_*289dupCACACACACACA		3_prime_UTR	Exon 42 of 42	NP_000539.2	P49815-1
	PKD1	NM_000296.4		c.*834_*845dupTGTGTGTGTGTG		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.*834_*845dupTGTGTGTGTGTG		3_prime_UTR	Exon 46 of 46	ENSP00000262304.4	P98161-1
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.*278_*289dupCACACACACACA		3_prime_UTR	Exon 42 of 42	ENSP00000219476.3	P49815-1
	PKD1	ENST00000423118.5	TSL:1	c.*834_*845dupTGTGTGTGTGTG		3_prime_UTR	Exon 46 of 46	ENSP00000399501.1	P98161-3

Frequencies

GnomAD3 genomes AF: 0.0000273 AC: 4 AN: 146614 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000670

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 4 AN: 274764 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 145206

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

African (AFR) AF: 0.00 AC: 0 AN: 7200

American (AMR) AF: 0.00 AC: 0 AN: 10080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8424

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 36226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1092

European-Non Finnish (NFE) AF: 0.0000245 AC: 4 AN: 163482

Other (OTH) AF: 0.00 AC: 0 AN: 15488

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000114836), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000273 AC: 4 AN: 146614 Hom.: 0 Cov.: 0 AF XY: 0.0000279 AC XY: 2 AN XY: 71642

African (AFR) AF: 0.0000268 AC: 1 AN: 37378

American (AMR) AF: 0.0000670 AC: 1 AN: 14932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67380

Other (OTH) AF: 0.00 AC: 0 AN: 2024

Alfa AF: 0.00 Hom.: 14

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36

Splicing

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

Other links and lift over

dbSNP: rs56279647; hg19: chr16-2138882;