chr16-2088881-GCA-G

Position:

• chr16-2088881-GCA-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001009944.3(PKD1):​c.*844_*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 0.012 in 414,776 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0095 (16 hom., cov: 0)
  • Exomes 𝑓: 0.013 (7 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.365

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-GCA-G is Benign according to our data. Variant chr16-2088881-GCA-G is described in ClinVar as [Likely_benign]. Clinvar id is 1218888.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00948 (1391/146672) while in subpopulation AFR AF= 0.033 (1236/37474). AF 95% confidence interval is 0.0315. There are 16 homozygotes in gnomad4. There are 695 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1391 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.*288_*289del		3_prime_UTR_variant	42/42	ENST00000219476.9	NP_000539.2
PKD1	NM_001009944.3	c.*844_*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.*288_*289del		3_prime_UTR_variant	42/42	5	NM_000548.5	ENSP00000219476
PKD1	ENST00000262304.9	c.*844_*845del		3_prime_UTR_variant	46/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes AF: 0.00940 AC: 1378 AN: 146568 Hom.: 15 Cov.: 0

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00335

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00527

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.0000967

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000891

Gnomad OTH AF: 0.00543

GnomAD4 exome AF: 0.0133 AC: 3570 AN: 268104 Hom.: 7 AF XY: 0.0130 AC XY: 1838 AN XY: 141488

Gnomad4 AFR exome AF: 0.0322

Gnomad4 AMR exome AF: 0.00998

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.0219

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.0121

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.00948 AC: 1391 AN: 146672 Hom.: 16 Cov.: 0 AF XY: 0.00969 AC XY: 695 AN XY: 71736

Gnomad4 AFR AF: 0.0330

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00528

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000967

Gnomad4 NFE AF: 0.000891

Gnomad4 OTH AF: 0.00538

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2019

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs56279647; hg19: chr16-2138882;