16-2088881-GCACACACACACA-GCACACACACACACACA

Variant names:

• chr16-2088881-G-GCACA
• rs56279647
• NM_001009944.3:c.*842_*845dupTGTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001009944.3(PKD1):​c.*842_*845dupTGTG 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 0.0060 (4 hom., cov: 0)
  • Exomes 𝑓: 0.0056 (3 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00596 (874/146694) while in subpopulation EAS AF = 0.0233 (119/5112). AF 95% confidence interval is 0.0199. There are 4 homozygotes in GnomAd4. There are 405 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*842_*845dupTGTG		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*286_*289dupCACA		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.*842_*845dupTGTG		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*286_*289dupCACA		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 879 AN: 146590 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.00276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00623

Gnomad ASJ AF: 0.0120

Gnomad EAS AF: 0.0232

Gnomad SAS AF: 0.00334

Gnomad FIN AF: 0.00126

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.00714

Gnomad OTH AF: 0.00544

GnomAD4 exome AF: 0.00564 AC: 1549 AN: 274622 Hom.: 3 Cov.: 0 AF XY: 0.00508 AC XY: 737 AN XY: 145140

African (AFR) AF: 0.00237 AC: 17 AN: 7178

American (AMR) AF: 0.00437 AC: 44 AN: 10072

Ashkenazi Jewish (ASJ) AF: 0.00855 AC: 72 AN: 8418

East Asian (EAS) AF: 0.0124 AC: 231 AN: 18704

South Asian (SAS) AF: 0.00168 AC: 61 AN: 36216

European-Finnish (FIN) AF: 0.00178 AC: 25 AN: 14050

Middle Eastern (MID) AF: 0.00733 AC: 8 AN: 1092

European-Non Finnish (NFE) AF: 0.00613 AC: 1002 AN: 163410

Other (OTH) AF: 0.00575 AC: 89 AN: 15482

GnomAD4 genome AF: 0.00596 AC: 874 AN: 146694 Hom.: 4 Cov.: 0 AF XY: 0.00564 AC XY: 405 AN XY: 71750

African (AFR) AF: 0.00270 AC: 101 AN: 37470

American (AMR) AF: 0.00622 AC: 93 AN: 14952

Ashkenazi Jewish (ASJ) AF: 0.0120 AC: 41 AN: 3424

East Asian (EAS) AF: 0.0233 AC: 119 AN: 5112

South Asian (SAS) AF: 0.00334 AC: 16 AN: 4786

European-Finnish (FIN) AF: 0.00126 AC: 13 AN: 10344

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.00712 AC: 480 AN: 67370

Other (OTH) AF: 0.00489 AC: 10 AN: 2044

Alfa AF: 0.00431 Hom.: 14

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism

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;