16-2088865-TCGCG-T

Variant names:

• chr16-2088865-TCGCG-T
• rs1178168657
• NM_001009944.3:c.*858_*861delCGCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001009944.3(PKD1):​c.*858_*861delCGCG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 526,576 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0960
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 16-2088865-TCGCG-T is Benign according to our data. Variant chr16-2088865-TCGCG-T is described in ClinVar as [Likely_benign]. Clinvar id is 1178576.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00349 (455/130460) while in subpopulation AFR AF = 0.0153 (415/27054). AF 95% confidence interval is 0.0141. There are 4 homozygotes in GnomAd4. There are 220 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.*858_*861delCGCG		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*258_*261delCGCG		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.*858_*861delCGCG		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*258_*261delCGCG		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 455 AN: 130378 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00185

Gnomad ASJ AF: 0.000925

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000622

Gnomad OTH AF: 0.00379

GnomAD4 exome AF: 0.000424 AC: 168 AN: 396116 Hom.: 1 AF XY: 0.000245 AC XY: 51 AN XY: 208306

African (AFR) AF: 0.0100 AC: 110 AN: 10962

American (AMR) AF: 0.000997 AC: 16 AN: 16042

Ashkenazi Jewish (ASJ) AF: 0.000652 AC: 8 AN: 12264

East Asian (EAS) AF: 0.00 AC: 0 AN: 27632

South Asian (SAS) AF: 0.00 AC: 0 AN: 44090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24288

Middle Eastern (MID) AF: 0.000579 AC: 1 AN: 1728

European-Non Finnish (NFE) AF: 0.0000381 AC: 9 AN: 236324

Other (OTH) AF: 0.00105 AC: 24 AN: 22786

GnomAD4 genome AF: 0.00349 AC: 455 AN: 130460 Hom.: 4 Cov.: 32 AF XY: 0.00346 AC XY: 220 AN XY: 63574

African (AFR) AF: 0.0153 AC: 415 AN: 27054

American (AMR) AF: 0.00185 AC: 25 AN: 13548

Ashkenazi Jewish (ASJ) AF: 0.000925 AC: 3 AN: 3244

East Asian (EAS) AF: 0.00 AC: 0 AN: 5032

South Asian (SAS) AF: 0.000215 AC: 1 AN: 4654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.0000622 AC: 4 AN: 64342

Other (OTH) AF: 0.00375 AC: 7 AN: 1868

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 17, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.096
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1178168657; hg19: chr16-2138866;