chr16-2088881-G-GCGCA

Variant names:

• chr16-2088881-G-GCGCA
• rs142285430
• NM_001009944.3:c.*845_*846insTGCG

Variant summary

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

The NM_001009944.3(PKD1):​c.*845_*846insTGCG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0031 (1 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365

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 nfe. gnomad4 allele frequency = 0.00365 (536/146696) while in subpopulation NFE AF= 0.00417 (281/67370). AF 95% confidence interval is 0.00377. There are 1 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 536 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*845_*846insTGCG		3_prime_UTR_variant	Exon 46 of 46	ENST00000262304.9	NP_001009944.3
TSC2	NM_000548.5	c.*272_*273insGCAC		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.*845_*846insTGCG		3_prime_UTR_variant	Exon 46 of 46	1	NM_001009944.3	ENSP00000262304.4
TSC2	ENST00000219476.9	c.*272_*273insGCAC		3_prime_UTR_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 535 AN: 146592 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00375

Gnomad ASJ AF: 0.00409

Gnomad EAS AF: 0.000976

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.00425

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.00417

Gnomad OTH AF: 0.000988

GnomAD4 exome AF: 0.00306 AC: 839 AN: 274282 Hom.: 1 Cov.: 0 AF XY: 0.00297 AC XY: 430 AN XY: 144962

Gnomad4 AFR exome AF: 0.00750

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00333

Gnomad4 EAS exome AF: 0.000801

Gnomad4 SAS exome AF: 0.000469

Gnomad4 FIN exome AF: 0.00378

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.00420

GnomAD4 genome AF: 0.00365 AC: 536 AN: 146696 Hom.: 1 Cov.: 0 AF XY: 0.00351 AC XY: 252 AN XY: 71748

Gnomad4 AFR AF: 0.00347

Gnomad4 AMR AF: 0.00375

Gnomad4 ASJ AF: 0.00409

Gnomad4 EAS AF: 0.000978

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.00425

Gnomad4 NFE AF: 0.00417

Gnomad4 OTH AF: 0.000978

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: rs142285430; hg19: chr16-2138882;