16-2091775-TC-TCCCC

Variant names:

• chr16-2091775-T-TCCC
• rs201204878
• NM_001009944.3:c.11537+3_11537+5dupGGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.11537+3_11537+5dupGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0076 in 1,609,866 control chromosomes in the GnomAD database, including 115 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (109 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.33
• Publications: 3 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]

PKD1-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 16-2091775-T-TCCC is Benign according to our data. Variant chr16-2091775-T-TCCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00644 (979/151994) while in subpopulation SAS AF = 0.0284 (137/4820). AF 95% confidence interval is 0.0245. There are 6 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.11537+3_11537+5dupGGG		splice_region intron	N/A	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.11534+3_11534+5dupGGG		splice_region intron	N/A	NP_000287.4
	PKD1-AS1	NR_135175.1		n.179+162_179+164dupCCC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.11537+5_11537+6insGGG		splice_region intron	N/A	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.11534+5_11534+6insGGG		splice_region intron	N/A	ENSP00000399501.1	P98161-3
	PKD1	ENST00000485120.1	TSL:3	n.526+5_526+6insGGG		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 977 AN: 151876 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.0280

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00899

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0101 AC: 2360 AN: 233058 AF XY: 0.0117

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00546

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.00491

Gnomad NFE exome AF: 0.00944

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00772 AC: 11256 AN: 1457872 Hom.: 109 Cov.: 32 AF XY: 0.00858 AC XY: 6222 AN XY: 725128

African (AFR) AF: 0.00135 AC: 45 AN: 33450

American (AMR) AF: 0.00546 AC: 243 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 454 AN: 25952

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39628

South Asian (SAS) AF: 0.0287 AC: 2461 AN: 85892

European-Finnish (FIN) AF: 0.00598 AC: 306 AN: 51212

Middle Eastern (MID) AF: 0.0374 AC: 211 AN: 5648

European-Non Finnish (NFE) AF: 0.00626 AC: 6955 AN: 1111382

Other (OTH) AF: 0.00962 AC: 579 AN: 60180

GnomAD4 genome AF: 0.00644 AC: 979 AN: 151994 Hom.: 6 Cov.: 33 AF XY: 0.00649 AC XY: 482 AN XY: 74316

African (AFR) AF: 0.00109 AC: 45 AN: 41420

American (AMR) AF: 0.00360 AC: 55 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3464

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5148

South Asian (SAS) AF: 0.0284 AC: 137 AN: 4820

European-Finnish (FIN) AF: 0.00302 AC: 32 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00899 AC: 611 AN: 67932

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00713 Hom.: 0

Bravo AF: 0.00567

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=93/7	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs201204878; hg19: chr16-2141776;