16-2088891-AC-A

Variant summary

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

The NM_001009944.3(PKD1):c.*835del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00417 in 446,960 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0094 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (8 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.293

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 16-2088891-AC-A is Benign according to our data. Variant chr16-2088891-AC-A is described in ClinVar as [Likely_benign]. Clinvar id is 1218692.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00944 (1385/146764) while in subpopulation AFR AF= 0.0344 (1254/36480). AF 95% confidence interval is 0.0328. There are 21 homozygotes in gnomad4. There are 670 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1375 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.*282del		3_prime_UTR_variant	42/42	ENST00000219476.9
PKD1	NM_001009944.3	c.*835del		3_prime_UTR_variant	46/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.*282del		3_prime_UTR_variant	42/42	5	NM_000548.5
PKD1	ENST00000262304.9	c.*835del		3_prime_UTR_variant	46/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00938 AC: 1375 AN: 146648 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00751

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00740

GnomAD4 exome AF: 0.00160 AC: 480 AN: 300196 Hom.: 8 Cov.: 0 AF XY: 0.00147 AC XY: 232 AN XY: 158154

Gnomad4 AFR exome AF: 0.0373

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00719

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000529

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.00944 AC: 1385 AN: 146764 Hom.: 21 Cov.: 33 AF XY: 0.00932 AC XY: 670 AN XY: 71900

Gnomad4 AFR AF: 0.0344

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00751

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00732

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 10, 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: rs1222652018; hg19: chr16-2138892;