rs374609310

chr16-2091558-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):c.11577G>T(p.Pro3859=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,533,076 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (13 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.24

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-2091558-C-A is Benign according to our data. Variant chr16-2091558-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 256907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000368 (56/151990) while in subpopulation SAS AF= 0.00973 (47/4830). AF 95% confidence interval is 0.00752. There are 1 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.11577G>T	p.Pro3859=	synonymous_variant	42/46	ENST00000262304.9
PKD1-AS1	NR_135175.1	n.123C>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.11577G>T	p.Pro3859=	synonymous_variant	42/46	1	NM_001009944.3	P5
PKD1-AS1	ENST00000563284.3	n.20C>A		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.000369 AC: 56 AN: 151876 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00972

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00183 AC: 261 AN: 142978 Hom.: 4 AF XY: 0.00235 AC XY: 189 AN XY: 80554

Gnomad AFR exome AF: 0.000273

Gnomad AMR exome AF: 0.0000444

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000769

Gnomad OTH exome AF: 0.000777

GnomAD4 exome AF: 0.000673 AC: 929 AN: 1381086 Hom.: 13 Cov.: 32 AF XY: 0.000964 AC XY: 659 AN XY: 683280

Gnomad4 AFR exome AF: 0.000165

Gnomad4 AMR exome AF: 0.0000301

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000275

Gnomad4 SAS exome AF: 0.0111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000258

Gnomad4 OTH exome AF: 0.000697

GnomAD4 genome AF: 0.000368 AC: 56 AN: 151990 Hom.: 1 Cov.: 33 AF XY: 0.000552 AC XY: 41 AN XY: 74314

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00973

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.0000945

Asia WGS AF: 0.00377 AC: 13 AN: 3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 18, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Polycystic kidney disease, adult type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	6.9
Dann	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs374609310; hg19: chr16-2141559;