NM_001009944.3:c.*853_*854dupGC

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001009944.3(PKD1):​c.*853_*854dupGC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 499,932 control chromosomes in the GnomAD database, including 16 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0076 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (12 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.04

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00763 (1090/142946) while in subpopulation AFR AF= 0.0212 (814/38314). AF 95% confidence interval is 0.02. There are 4 homozygotes in gnomad4. There are 528 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1090 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*853_*854dupGC		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*271_*272dupGC		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	c.*853_*854dupGC		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*271_*272dupGC		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00758 AC: 1082 AN: 142838 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00605

Gnomad ASJ AF: 0.00760

Gnomad EAS AF: 0.00463

Gnomad SAS AF: 0.00713

Gnomad FIN AF: 0.000303

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.00920

GnomAD4 exome AF: 0.00588 AC: 2099 AN: 356986 Hom.: 12 Cov.: 0 AF XY: 0.00577 AC XY: 1084 AN XY: 187998

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.00666

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.00257

Gnomad4 SAS exome AF: 0.00471

Gnomad4 FIN exome AF: 0.00653

Gnomad4 NFE exome AF: 0.00511

Gnomad4 OTH exome AF: 0.00743

GnomAD4 genome AF: 0.00763 AC: 1090 AN: 142946 Hom.: 4 Cov.: 33 AF XY: 0.00755 AC XY: 528 AN XY: 69918

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.00604

Gnomad4 ASJ AF: 0.00760

Gnomad4 EAS AF: 0.00464

Gnomad4 SAS AF: 0.00713

Gnomad4 FIN AF: 0.000303

Gnomad4 NFE AF: 0.00135

Gnomad4 OTH AF: 0.00910

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs561630495; hg19: chr16-2138873;