chr16-2088881-G-GCACACA

Variant names:

• chr16-2088881-G-GCACACA
• rs56279647
• NM_001009944.3:c.*840_*845dupTGTGTG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001009944.3(PKD1):​c.*840_*845dupTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00044 (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: 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00123 (181/146708) while in subpopulation AFR AF = 0.00392 (147/37480). AF 95% confidence interval is 0.0034. There are 1 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*840_*845dupTGTGTG		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*284_*289dupCACACA		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.*840_*845dupTGTGTG		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*284_*289dupCACACA		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 181 AN: 146604 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000536

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000585

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000312

Gnomad OTH AF: 0.000988

GnomAD4 exome AF: 0.000444 AC: 122 AN: 274708 Hom.: 0 Cov.: 0 AF XY: 0.000393 AC XY: 57 AN XY: 145178

African (AFR) AF: 0.00334 AC: 24 AN: 7196

American (AMR) AF: 0.000496 AC: 5 AN: 10080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8420

East Asian (EAS) AF: 0.000427 AC: 8 AN: 18716

South Asian (SAS) AF: 0.000138 AC: 5 AN: 36224

European-Finnish (FIN) AF: 0.0000712 AC: 1 AN: 14054

Middle Eastern (MID) AF: 0.00183 AC: 2 AN: 1090

European-Non Finnish (NFE) AF: 0.000416 AC: 68 AN: 163444

Other (OTH) AF: 0.000581 AC: 9 AN: 15484

GnomAD4 genome AF: 0.00123 AC: 181 AN: 146708 Hom.: 1 Cov.: 0 AF XY: 0.00124 AC XY: 89 AN XY: 71754

African (AFR) AF: 0.00392 AC: 147 AN: 37480

American (AMR) AF: 0.000535 AC: 8 AN: 14950

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

East Asian (EAS) AF: 0.000587 AC: 3 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000312 AC: 21 AN: 67372

Other (OTH) AF: 0.000978 AC: 2 AN: 2046

Alfa AF: 0.00 Hom.: 14

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;