rs35842

Positions:

• chr16-2117873-G-A
• chr16-2117873-G-C
• chr16-2117873-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000262304.9(PKD1):​c.1119C>T​(p.Leu373=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 142,122 control chromosomes in the GnomAD database, including 48,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (48164 hom., cov: 30)
  • Exomes 𝑓: 0.78 (295723 hom.)
  • Failed GnomAD Quality Control
• Consequence: PKD1 ENST00000262304.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.08

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-2117873-G-A is Benign according to our data. Variant chr16-2117873-G-A is described in ClinVar as [Benign]. Clinvar id is 803174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2117873-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.94 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.1119C>T	p.Leu373=	synonymous_variant	5/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.1119C>T	p.Leu373=	synonymous_variant	5/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes AF: 0.829 AC: 117786 AN: 142016 Hom.: 48111 Cov.: 30

Gnomad AFR AF: 0.906

Gnomad AMI AF: 0.710

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.963

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.814

Gnomad MID AF: 0.825

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.815

GnomAD3 exomes AF: 0.895 AC: 84660 AN: 94572 Hom.: 38124 AF XY: 0.894 AC XY: 44281 AN XY: 49514

Gnomad AFR exome AF: 0.974

Gnomad AMR exome AF: 0.930

Gnomad ASJ exome AF: 0.820

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.942

Gnomad FIN exome AF: 0.847

Gnomad NFE exome AF: 0.829

Gnomad OTH exome AF: 0.860

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.778 AC: 788669 AN: 1014150 Hom.: 295723 Cov.: 15 AF XY: 0.779 AC XY: 399855 AN XY: 513052

Gnomad4 AFR exome AF: 0.890

Gnomad4 AMR exome AF: 0.879

Gnomad4 ASJ exome AF: 0.756

Gnomad4 EAS exome AF: 0.914

Gnomad4 SAS exome AF: 0.842

Gnomad4 FIN exome AF: 0.799

Gnomad4 NFE exome AF: 0.756

Gnomad4 OTH exome AF: 0.792

GnomAD4 genome AF: 0.830 AC: 117892 AN: 142122 Hom.: 48164 Cov.: 30 AF XY: 0.833 AC XY: 57768 AN XY: 69370

Gnomad4 AFR AF: 0.906

Gnomad4 AMR AF: 0.856

Gnomad4 ASJ AF: 0.767

Gnomad4 EAS AF: 0.963

Gnomad4 SAS AF: 0.888

Gnomad4 FIN AF: 0.814

Gnomad4 NFE AF: 0.771

Gnomad4 OTH AF: 0.817

Alfa AF: 0.802 Hom.: 4452

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.85
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs35842; hg19: chr16-2167874; COSMIC: COSV51919086; COSMIC: COSV51919086;