rs2575313

Variant names:

• chr16-2109404-C-T
• rs2575313
• NM_001009944.3:c.5763G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.5763G>A​(p.Leu1921Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,600,104 control chromosomes in the GnomAD database, including 1,705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (113 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1592 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.352
• Publications: 11 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 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 16-2109404-C-T is Benign according to our data. Variant chr16-2109404-C-T is described in ClinVar as Benign. ClinVar VariationId is 256981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.352 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0312 (4748/152354) while in subpopulation NFE AF = 0.0469 (3190/68032). AF 95% confidence interval is 0.0455. There are 113 homozygotes in GnomAd4. There are 2345 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 113 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.5763G>A	p.Leu1921Leu	synonymous	Exon 15 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.5763G>A	p.Leu1921Leu	synonymous	Exon 15 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.5763G>A	p.Leu1921Leu	synonymous	Exon 15 of 46	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.5763G>A	p.Leu1921Leu	synonymous	Exon 15 of 46	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.471-1046G>A		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4749 AN: 152236 Hom.: 113 Cov.: 33

Gnomad AFR AF: 0.00810

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.0740

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0469

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0308 AC: 7168 AN: 232416 AF XY: 0.0311

Gnomad AFR exome AF: 0.00648

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0742

Gnomad NFE exome AF: 0.0469

Gnomad OTH exome AF: 0.0325

GnomAD4 exome AF: 0.0433 AC: 62753 AN: 1447750 Hom.: 1592 Cov.: 35 AF XY: 0.0423 AC XY: 30484 AN XY: 720262

African (AFR) AF: 0.00635 AC: 212 AN: 33384

American (AMR) AF: 0.0165 AC: 735 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.0172 AC: 449 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00424 AC: 365 AN: 86088

European-Finnish (FIN) AF: 0.0756 AC: 3299 AN: 43640

Middle Eastern (MID) AF: 0.00876 AC: 37 AN: 4226

European-Non Finnish (NFE) AF: 0.0500 AC: 55488 AN: 1110106

Other (OTH) AF: 0.0361 AC: 2168 AN: 59984

GnomAD4 genome AF: 0.0312 AC: 4748 AN: 152354 Hom.: 113 Cov.: 33 AF XY: 0.0315 AC XY: 2345 AN XY: 74492

African (AFR) AF: 0.00808 AC: 336 AN: 41588

American (AMR) AF: 0.0203 AC: 311 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4834

European-Finnish (FIN) AF: 0.0740 AC: 786 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0469 AC: 3190 AN: 68032

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0382 Hom.: 31

Bravo AF: 0.0260

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0451

EpiControl AF: 0.0417

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.5
DANN	Benign	0.85
PhyloP100		0.35
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2575313; hg19: chr16-2159405;