chr16-2088885-A-G

Variant names:

• chr16-2088885-A-G
• rs549700419
• NM_001009944.3:c.*842T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001009944.3(PKD1):​c.*842T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 327,810 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (7 hom., cov: 30)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.770
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-2088885-A-G is Benign according to our data. Variant chr16-2088885-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1216114.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00743 (828/111384) while in subpopulation AFR AF = 0.0236 (782/33092). AF 95% confidence interval is 0.0223. There are 7 homozygotes in GnomAd4. There are 424 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*842T>C		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*275A>G		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.*842T>C		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*275A>G		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 821 AN: 111270 Hom.: 6 Cov.: 30

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00240

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.000522

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000654

Gnomad OTH AF: 0.00708

GnomAD4 exome AF: 0.00116 AC: 252 AN: 216426 Hom.: 2 Cov.: 0 AF XY: 0.00112 AC XY: 129 AN XY: 114786

African (AFR) AF: 0.0191 AC: 152 AN: 7952

American (AMR) AF: 0.00175 AC: 16 AN: 9120

Ashkenazi Jewish (ASJ) AF: 0.000161 AC: 1 AN: 6204

East Asian (EAS) AF: 0.000898 AC: 18 AN: 20036

South Asian (SAS) AF: 0.000408 AC: 12 AN: 29412

European-Finnish (FIN) AF: 0.000198 AC: 2 AN: 10084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 948

European-Non Finnish (NFE) AF: 0.000174 AC: 21 AN: 120496

Other (OTH) AF: 0.00246 AC: 30 AN: 12174

GnomAD4 genome AF: 0.00743 AC: 828 AN: 111384 Hom.: 7 Cov.: 30 AF XY: 0.00777 AC XY: 424 AN XY: 54576

African (AFR) AF: 0.0236 AC: 782 AN: 33092

American (AMR) AF: 0.00240 AC: 29 AN: 12082

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2344

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5114

South Asian (SAS) AF: 0.000262 AC: 1 AN: 3824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000654 AC: 3 AN: 45888

Other (OTH) AF: 0.00698 AC: 11 AN: 1576

Alfa AF: 0.00438 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.38
PhyloP100		-0.77
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.3
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: rs549700419; hg19: chr16-2138886;