16-2088881-GCACACA-G

Position:

• chr16-2088881-GCACACA-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001009944.3(PKD1):​c.*840_*845del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0796 in 421,114 control chromosomes in the GnomAD database, including 1,639 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.072 (490 hom., cov: 0)
  • Exomes 𝑓: 0.084 (1149 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.411

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 16-2088881-GCACACA-G is Benign according to our data. Variant chr16-2088881-GCACACA-G is described in ClinVar as [Benign]. Clinvar id is 1049696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.*284_*289del		3_prime_UTR_variant	42/42	ENST00000219476.9	NP_000539.2
PKD1	NM_001009944.3	c.*840_*845del		3_prime_UTR_variant	46/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.*284_*289del		3_prime_UTR_variant	42/42	5	NM_000548.5	ENSP00000219476
PKD1	ENST00000262304.9	c.*840_*845del		3_prime_UTR_variant	46/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10514 AN: 146582 Hom.: 492 Cov.: 0

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.0476

Gnomad AMR AF: 0.0592

Gnomad ASJ AF: 0.0958

Gnomad EAS AF: 0.000976

Gnomad SAS AF: 0.0545

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0903

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0767

GnomAD4 exome AF: 0.0839 AC: 23032 AN: 274428 Hom.: 1149 AF XY: 0.0816 AC XY: 11834 AN XY: 145024

Gnomad4 AFR exome AF: 0.0197

Gnomad4 AMR exome AF: 0.0548

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.000214

Gnomad4 SAS exome AF: 0.0565

Gnomad4 FIN exome AF: 0.0869

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.0892

GnomAD4 genome AF: 0.0716 AC: 10509 AN: 146686 Hom.: 490 Cov.: 0 AF XY: 0.0698 AC XY: 5008 AN XY: 71742

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.0591

Gnomad4 ASJ AF: 0.0958

Gnomad4 EAS AF: 0.000978

Gnomad4 SAS AF: 0.0554

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.0758

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 12, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs56279647; hg19: chr16-2138882;