rs145776888

Positions:

• chr16-2117551-C-T

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.1323G>A​(p.Gly441=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,601,694 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (25 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.584

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=-0.5).
• BP6: Variant 16-2117551-C-T is Benign according to our data. Variant chr16-2117551-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2117551-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.584 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00826 (1259/152350) while in subpopulation AFR AF= 0.0287 (1192/41584). AF 95% confidence interval is 0.0273. There are 15 homozygotes in gnomad4. There are 574 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1259 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.1323G>A	p.Gly441=	synonymous_variant	6/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.1323G>A	p.Gly441=	synonymous_variant	6/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes AF: 0.00825 AC: 1256 AN: 152232 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00208 AC: 414 AN: 198918 Hom.: 10 AF XY: 0.00162 AC XY: 176 AN XY: 108956

Gnomad AFR exome AF: 0.0333

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000754

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000937

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.000945 AC: 1369 AN: 1449344 Hom.: 25 Cov.: 33 AF XY: 0.000847 AC XY: 610 AN XY: 720350

Gnomad4 AFR exome AF: 0.0338

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000471

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000524

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00826 AC: 1259 AN: 152350 Hom.: 15 Cov.: 33 AF XY: 0.00771 AC XY: 574 AN XY: 74490

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00257 Hom.: 0

Bravo AF: 0.00959

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2019	This variant is associated with the following publications: (PMID: 22008521, 17574468) -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2022	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease, adult type Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 28, 2020	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Gly441= variant was identified in 2 of 238 proband chromosomes (frequency: 0.008) from individuals or families with ADPKD (Bataille 2011, Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs145776888) as "With Benign allele", ClinVar (classified as benign by Prevention Genetics and Athena Diagnostics), and in ADPKD Mutation Database (as likely neutral). The variant was not identified in LOVD 3.0 or PKD1-LOVD databases. The variant was identified in control databases in 639 of 224986 chromosomes (11 homozygous) at a frequency of 0.003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 579 of 18934 chromosomes (freq: 0.03), Other in 7 of 5530 chromosomes (freq: 0.001), Latino in 41 of 30268 chromosomes (freq: 0.001), European in 10 of 98026 chromosomes (freq: 0.0001), and South Asian in 2 of 26670 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Gly441= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.9
DANN	Benign	0.71
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: rs145776888; hg19: chr16-2167552;