16-2088881-GCACACACACACA-GCACACA

Variant names:

• chr16-2088881-GCACACA-G
• rs56279647
• NM_001009944.3:c.*840_*845delTGTGTG

Variant summary

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

The NM_001009944.3(PKD1):​c.*840_*845delTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0796 in 421,114 control chromosomes in the GnomAD database, including 1,639 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.072 (490 hom., cov: 0)
  • Exomes 𝑓: 0.084 (1149 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.411
• 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-GCACACA-G is Benign according to our data. Variant chr16-2088881-GCACACA-G is described in ClinVar as Benign. ClinVar VariationId is 1049696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.101 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.*840_*845delTGTGTG		3_prime_UTR	Exon 46 of 46	NP_001009944.3	P98161-1
	TSC2	NM_000548.5	MANE Select	c.*284_*289delCACACA		3_prime_UTR	Exon 42 of 42	NP_000539.2	P49815-1
	PKD1	NM_000296.4		c.*840_*845delTGTGTG		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.*840_*845delTGTGTG		3_prime_UTR	Exon 46 of 46	ENSP00000262304.4	P98161-1
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.*284_*289delCACACA		3_prime_UTR	Exon 42 of 42	ENSP00000219476.3	P49815-1
	PKD1	ENST00000423118.5	TSL:1	c.*840_*845delTGTGTG		3_prime_UTR	Exon 46 of 46	ENSP00000399501.1	P98161-3

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10514 AN: 146582 Hom.: 492 Cov.: 0

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.0476

Gnomad AMR AF: 0.0592

Gnomad ASJ AF: 0.0958

Gnomad EAS AF: 0.000976

Gnomad SAS AF: 0.0545

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0903

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0767

GnomAD4 exome AF: 0.0839 AC: 23032 AN: 274428 Hom.: 1149 AF XY: 0.0816 AC XY: 11834 AN XY: 145024

African (AFR) AF: 0.0197 AC: 142 AN: 7200

American (AMR) AF: 0.0548 AC: 552 AN: 10076

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 881 AN: 8414

East Asian (EAS) AF: 0.000214 AC: 4 AN: 18718

South Asian (SAS) AF: 0.0565 AC: 2043 AN: 36188

European-Finnish (FIN) AF: 0.0869 AC: 1220 AN: 14034

Middle Eastern (MID) AF: 0.107 AC: 117 AN: 1090

European-Non Finnish (NFE) AF: 0.102 AC: 16694 AN: 163242

Other (OTH) AF: 0.0892 AC: 1379 AN: 15466

GnomAD4 genome AF: 0.0716 AC: 10509 AN: 146686 Hom.: 490 Cov.: 0 AF XY: 0.0698 AC XY: 5008 AN XY: 71742

African (AFR) AF: 0.0198 AC: 743 AN: 37482

American (AMR) AF: 0.0591 AC: 884 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.0958 AC: 328 AN: 3424

East Asian (EAS) AF: 0.000978 AC: 5 AN: 5112

South Asian (SAS) AF: 0.0554 AC: 265 AN: 4786

European-Finnish (FIN) AF: 0.109 AC: 1123 AN: 10338

Middle Eastern (MID) AF: 0.0833 AC: 24 AN: 288

European-Non Finnish (NFE) AF: 0.103 AC: 6939 AN: 67358

Other (OTH) AF: 0.0758 AC: 155 AN: 2044

Alfa AF: 0.0286 Hom.: 14

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.41
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;