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. The variant received -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
• 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: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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

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

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

African (AFR) AF: 0.0240 AC: 223 AN: 9288

American (AMR) AF: 0.00666 AC: 96 AN: 14406

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 128 AN: 11034

East Asian (EAS) AF: 0.00257 AC: 63 AN: 24474

South Asian (SAS) AF: 0.00471 AC: 203 AN: 43122

European-Finnish (FIN) AF: 0.00653 AC: 134 AN: 20516

Middle Eastern (MID) AF: 0.0100 AC: 15 AN: 1500

European-Non Finnish (NFE) AF: 0.00511 AC: 1085 AN: 212190

Other (OTH) AF: 0.00743 AC: 152 AN: 20456

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0212 AC: 814 AN: 38314

American (AMR) AF: 0.00604 AC: 86 AN: 14228

Ashkenazi Jewish (ASJ) AF: 0.00760 AC: 25 AN: 3290

East Asian (EAS) AF: 0.00464 AC: 23 AN: 4956

South Asian (SAS) AF: 0.00713 AC: 33 AN: 4628

European-Finnish (FIN) AF: 0.000303 AC: 3 AN: 9900

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.00135 AC: 87 AN: 64470

Other (OTH) AF: 0.00910 AC: 18 AN: 1978

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-6.0
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs561630495; hg19: chr16-2138873;