16-2088872-TGCGCGCGC-TGCGCGC

Variant names:

• chr16-2088872-TGC-T
• rs561630495
• NM_001009944.3:c.*853_*854delGC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001009944.3(PKD1):​c.*853_*854delGC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00048 in 500,250 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (1 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0950
• 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: 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000231 (33/142976) while in subpopulation EAS AF = 0.00161 (8/4956). AF 95% confidence interval is 0.000803. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.*853_*854delGC		3_prime_UTR	Exon 46 of 46	NP_001009944.3	P98161-1
	TSC2	NM_000548.5	MANE Select	c.*271_*272delGC		3_prime_UTR	Exon 42 of 42	NP_000539.2	P49815-1
	PKD1	NM_000296.4		c.*853_*854delGC		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.*853_*854delGC		3_prime_UTR	Exon 46 of 46	ENSP00000262304.4	P98161-1
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.*271_*272delGC		3_prime_UTR	Exon 42 of 42	ENSP00000219476.3	P49815-1
	PKD1	ENST00000423118.5	TSL:1	c.*853_*854delGC		3_prime_UTR	Exon 46 of 46	ENSP00000399501.1	P98161-3

Frequencies

GnomAD3 genomes AF: 0.000231 AC: 33 AN: 142866 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000352

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00161

Gnomad SAS AF: 0.000216

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000465

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000579 AC: 207 AN: 357274 Hom.: 1 AF XY: 0.000500 AC XY: 94 AN XY: 188168

African (AFR) AF: 0.000748 AC: 7 AN: 9360

American (AMR) AF: 0.000347 AC: 5 AN: 14428

Ashkenazi Jewish (ASJ) AF: 0.0000904 AC: 1 AN: 11058

East Asian (EAS) AF: 0.00486 AC: 119 AN: 24466

South Asian (SAS) AF: 0.000487 AC: 21 AN: 43144

European-Finnish (FIN) AF: 0.000292 AC: 6 AN: 20532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1500

European-Non Finnish (NFE) AF: 0.000203 AC: 43 AN: 212314

Other (OTH) AF: 0.000244 AC: 5 AN: 20472

GnomAD4 genome AF: 0.000231 AC: 33 AN: 142976 Hom.: 0 Cov.: 33 AF XY: 0.000214 AC XY: 15 AN XY: 69942

African (AFR) AF: 0.000417 AC: 16 AN: 38338

American (AMR) AF: 0.000351 AC: 5 AN: 14230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3290

East Asian (EAS) AF: 0.00161 AC: 8 AN: 4956

South Asian (SAS) AF: 0.000216 AC: 1 AN: 4628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000465 AC: 3 AN: 64474

Other (OTH) AF: 0.00 AC: 0 AN: 1978

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000174

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.095

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: rs561630495; hg19: chr16-2138873;