16-2088737-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1 O:1
• Conservation: PhyloP100: 0.421

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 -14 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_single_submitter, 1 stars. Variant chr16-2088737-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 2686 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.*127T>C		3_prime_UTR_variant	42/42	ENST00000219476.9
PKD1	NM_001009944.3	c.*990A>G		3_prime_UTR_variant	46/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.*127T>C		3_prime_UTR_variant	42/42	5	NM_000548.5
PKD1	ENST00000262304.9	c.*990A>G		3_prime_UTR_variant	46/46	1	NM_001009944.3	P5

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

Gnomad4 AFR exome AF: 0.00249

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.0652

Gnomad4 EAS exome AF: 0.000291

Gnomad4 SAS exome AF: 0.0304

Gnomad4 FIN exome AF: 0.0179

Gnomad4 NFE exome AF: 0.0231

Gnomad4 OTH exome AF: 0.0246

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

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.0598

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.0304

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.0253

Gnomad4 OTH AF: 0.0166

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:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

- -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	14
Dann	Benign	0.56

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: rs34379884; hg19: chr16-2138738;