16-2088881-G-GCGCA

Variant names:

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

Variant summary

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

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
• 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, 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 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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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	ENST00000262304.9	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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00750 AC: 53 AN: 7062

American (AMR) AF: 0.00179 AC: 18 AN: 10068

Ashkenazi Jewish (ASJ) AF: 0.00333 AC: 28 AN: 8396

East Asian (EAS) AF: 0.000801 AC: 15 AN: 18718

South Asian (SAS) AF: 0.000469 AC: 17 AN: 36212

European-Finnish (FIN) AF: 0.00378 AC: 53 AN: 14038

Middle Eastern (MID) AF: 0.00184 AC: 2 AN: 1088

European-Non Finnish (NFE) AF: 0.00360 AC: 588 AN: 163238

Other (OTH) AF: 0.00420 AC: 65 AN: 15462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00347 AC: 130 AN: 37468

American (AMR) AF: 0.00375 AC: 56 AN: 14952

Ashkenazi Jewish (ASJ) AF: 0.00409 AC: 14 AN: 3424

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

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4786

European-Finnish (FIN) AF: 0.00425 AC: 44 AN: 10346

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.00417 AC: 281 AN: 67370

Other (OTH) AF: 0.000978 AC: 2 AN: 2046

Alfa AF: 0.00 Hom.: 9

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36

Splicing

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

Other links and lift over

dbSNP: rs142285430; hg19: chr16-2138882;