16-2088881-GCACACACACACA-GCACACACACACACA

Variant names:

• chr16-2088881-G-GCA
• rs56279647
• NM_001009944.3:c.*844_*845dupTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001009944.3(PKD1):​c.*844_*845dupTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.045 (274 hom., cov: 0)
  • Exomes 𝑓: 0.042 (209 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.365
• Publications: 1 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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 -10 ACMG points.

• BP6: Variant 16-2088881-G-GCA is Benign according to our data. Variant chr16-2088881-G-GCA is described in ClinVar as Likely_benign. ClinVar VariationId is 1217705.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.*844_*845dupTG		3_prime_UTR	Exon 46 of 46	NP_001009944.3	P98161-1
	TSC2	NM_000548.5	MANE Select	c.*288_*289dupCA		3_prime_UTR	Exon 42 of 42	NP_000539.2	P49815-1
	PKD1	NM_000296.4		c.*844_*845dupTG		3_prime_UTR	Exon 46 of 46	NP_000287.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.*844_*845dupTG		3_prime_UTR	Exon 46 of 46	ENSP00000262304.4	P98161-1
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.*288_*289dupCA		3_prime_UTR	Exon 42 of 42	ENSP00000219476.3	P49815-1
	PKD1	ENST00000423118.5	TSL:1	c.*844_*845dupTG		3_prime_UTR	Exon 46 of 46	ENSP00000399501.1	P98161-3

Frequencies

GnomAD3 genomes AF: 0.0452 AC: 6623 AN: 146594 Hom.: 273 Cov.: 0

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00221

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.0275

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.0474

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.0452

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0519

GnomAD4 exome AF: 0.0421 AC: 11556 AN: 274228 Hom.: 209 Cov.: 0 AF XY: 0.0415 AC XY: 6019 AN XY: 144900

African (AFR) AF: 0.0206 AC: 148 AN: 7194

American (AMR) AF: 0.139 AC: 1398 AN: 10042

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 180 AN: 8408

East Asian (EAS) AF: 0.144 AC: 2681 AN: 18630

South Asian (SAS) AF: 0.0334 AC: 1207 AN: 36154

European-Finnish (FIN) AF: 0.0239 AC: 336 AN: 14032

Middle Eastern (MID) AF: 0.0559 AC: 61 AN: 1092

European-Non Finnish (NFE) AF: 0.0301 AC: 4918 AN: 163214

Other (OTH) AF: 0.0406 AC: 627 AN: 15462

GnomAD4 genome AF: 0.0452 AC: 6626 AN: 146698 Hom.: 274 Cov.: 0 AF XY: 0.0464 AC XY: 3328 AN XY: 71752

African (AFR) AF: 0.0212 AC: 794 AN: 37472

American (AMR) AF: 0.130 AC: 1943 AN: 14952

Ashkenazi Jewish (ASJ) AF: 0.0275 AC: 94 AN: 3424

East Asian (EAS) AF: 0.140 AC: 713 AN: 5108

South Asian (SAS) AF: 0.0468 AC: 224 AN: 4786

European-Finnish (FIN) AF: 0.0309 AC: 320 AN: 10348

Middle Eastern (MID) AF: 0.0417 AC: 12 AN: 288

European-Non Finnish (NFE) AF: 0.0359 AC: 2419 AN: 67370

Other (OTH) AF: 0.0513 AC: 105 AN: 2046

Alfa AF: 0.0119 Hom.: 14

Bravo AF: 0.0514

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56279647; hg19: chr16-2138882;