chr16-2088872-T-TGCGC

Position:

• chr16-2088872-T-TGCGC

Variant summary

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

The NM_001009944.3(PKD1):​c.*854_*855insGCGC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 500,478 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (1 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -6.04

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 16-2088872-T-TGCGC is Benign according to our data. Variant chr16-2088872-T-TGCGC is described in ClinVar as [Likely_benign]. Clinvar id is 1180280.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00321 (459/142968) while in subpopulation AFR AF= 0.0113 (432/38330). AF 95% confidence interval is 0.0104. There are 5 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 459 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.*269_*272dup		3_prime_UTR_variant	42/42	ENST00000219476.9
PKD1	NM_001009944.3	c.*854_*855insGCGC		3_prime_UTR_variant	46/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.*269_*272dup		3_prime_UTR_variant	42/42	5	NM_000548.5
PKD1	ENST00000262304.9	c.*854_*855insGCGC		3_prime_UTR_variant	46/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.00318 AC: 455 AN: 142858 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000704

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000648

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.000109

Gnomad OTH AF: 0.00256

GnomAD4 exome AF: 0.000408 AC: 146 AN: 357510 Hom.: 1 Cov.: 0 AF XY: 0.000366 AC XY: 69 AN XY: 188276

Gnomad4 AFR exome AF: 0.00791

Gnomad4 AMR exome AF: 0.000624

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.000342

GnomAD4 genome AF: 0.00321 AC: 459 AN: 142968 Hom.: 5 Cov.: 33 AF XY: 0.00319 AC XY: 223 AN XY: 69942

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.000703

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000648

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000109

Gnomad4 OTH AF: 0.00253

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 15, 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: rs561630495; hg19: chr16-2138873;