16-2088737-T-C

Variant names:

• chr16-2088737-T-C
• rs34379884
• NM_001009944.3:c.*990A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.*990A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,321,668 control chromosomes in the GnomAD database, including 424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (37 hom., cov: 33)
  • Exomes 𝑓: 0.023 (387 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.421
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-2088737-T-C is Benign according to our data. Variant chr16-2088737-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 65144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0177 (2687/152064) while in subpopulation SAS AF = 0.0304 (147/4830). AF 95% confidence interval is 0.0264. There are 37 homozygotes in GnomAd4. There are 1304 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*990A>G		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*127T>C		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.*990A>G		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*127T>C		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2686 AN: 151946 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.0598

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0300

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0252

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.0228 AC: 26677 AN: 1169604 Hom.: 387 Cov.: 16 AF XY: 0.0234 AC XY: 13537 AN XY: 579532

African (AFR) AF: 0.00249 AC: 66 AN: 26482

American (AMR) AF: 0.0113 AC: 343 AN: 30432

Ashkenazi Jewish (ASJ) AF: 0.0652 AC: 1407 AN: 21582

East Asian (EAS) AF: 0.000291 AC: 10 AN: 34342

South Asian (SAS) AF: 0.0304 AC: 2092 AN: 68754

European-Finnish (FIN) AF: 0.0179 AC: 575 AN: 32160

Middle Eastern (MID) AF: 0.0319 AC: 138 AN: 4324

European-Non Finnish (NFE) AF: 0.0231 AC: 20810 AN: 901380

Other (OTH) AF: 0.0246 AC: 1236 AN: 50148

GnomAD4 genome AF: 0.0177 AC: 2687 AN: 152064 Hom.: 37 Cov.: 33 AF XY: 0.0175 AC XY: 1304 AN XY: 74350

African (AFR) AF: 0.00361 AC: 150 AN: 41518

American (AMR) AF: 0.0140 AC: 213 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0598 AC: 207 AN: 3464

East Asian (EAS) AF: 0.000967 AC: 5 AN: 5172

South Asian (SAS) AF: 0.0304 AC: 147 AN: 4830

European-Finnish (FIN) AF: 0.0181 AC: 191 AN: 10576

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0253 AC: 1716 AN: 67960

Other (OTH) AF: 0.0166 AC: 35 AN: 2104

Alfa AF: 0.0232 Hom.: 7

Bravo AF: 0.0160

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	14
DANN	Benign	0.56
PhyloP100		0.42
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: rs34379884; hg19: chr16-2138738;