rs62038811

Positions:

• chr16-2089874-G-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.12765C>T​(p.Pro4255=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00662 in 1,609,788 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0069 (48 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.62

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=-0.85).
• BP6: Variant 16-2089874-G-A is Benign according to our data. Variant chr16-2089874-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2089874-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.62 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00426 (649/152354) while in subpopulation NFE AF= 0.00783 (533/68032). AF 95% confidence interval is 0.00728. There are 1 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 649 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.12765C>T	p.Pro4255=	synonymous_variant	46/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.12765C>T	p.Pro4255=	synonymous_variant	46/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.12762C>T	p.Pro4254=	synonymous_variant	46/46	1		ENSP00000399501	A2
PKD1	ENST00000472577.1	n.793C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00427 AC: 650 AN: 152240 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00178

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00783

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00379 AC: 891 AN: 235318 Hom.: 2 AF XY: 0.00402 AC XY: 518 AN XY: 128950

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000313

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000301

Gnomad FIN exome AF: 0.000594

Gnomad NFE exome AF: 0.00767

Gnomad OTH exome AF: 0.00122

GnomAD4 exome AF: 0.00687 AC: 10013 AN: 1457434 Hom.: 48 Cov.: 31 AF XY: 0.00681 AC XY: 4938 AN XY: 724876

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00124

Gnomad4 ASJ exome AF: 0.000308

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000222

Gnomad4 FIN exome AF: 0.000892

Gnomad4 NFE exome AF: 0.00858

Gnomad4 OTH exome AF: 0.00532

GnomAD4 genome AF: 0.00426 AC: 649 AN: 152354 Hom.: 1 Cov.: 34 AF XY: 0.00360 AC XY: 268 AN XY: 74498

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00783

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00546 Hom.: 1

Bravo AF: 0.00448

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PKD1: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2020	This variant is associated with the following publications: (PMID: 10200984, 11058904, 22008521, 22383692) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 11, 2021	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Pro4255= variant was identified in 16 of 1176 proband chromosomes (frequency: 0.014) from Spanish, Slovenian, Italian, American and French individuals or families with ADPKD, and considered to be a polymorphism based on being a silent change or through family studies (Aguiari 2000, Badenas 1999, Vouk 2006, Tan 2009, Bataille 2011, Rossetti 2001, Rossetti 2012). The variant was also identified in dbSNP (ID: rs62038811) “NA”, ADPKD Mutation Database (classification likely neutral), 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.0014), HAP-MAP populations: HAPMAP-EUR in 5 of 1006 chromosomes (frequency: 0.005), HAPMAP-AFR in 1 of 1322 chromosomes (frequency: 0.0008), HAPMAP-AMR in 1 of 694 chromosomes (frequency: 0.0014), in the NHLBI GO Exome Sequencing Project in 48 of 8542 European American (frequency: 0.0056) and in 12 of 4334 (frequency: 0.0028) African American alleles; and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 374 (1 homozygous) of 48494 chromosomes (frequency: 0.0077) from a population of European (Non-Finnish), in 5 of 3334 chromosomes (frequency: 0.0015) from Europe (Finnish), in 9 of 6810 chromosomes from African, in 9 of 7788 chromosomes (frequency: 0.0012) from Latin regions and in 6 of 13494 chromosomes (frequency: 0.0004) from South Asia, increasing the likelihood this could be a low frequency benign variant. The variant was not identified in East Asian or other populations in the ExAC database. In addition the variant was identified with a co-occurring pathogenic PKD1 variant (p.Trp1243X) by our laboratory in a patient with ADPKD, increasing the likelihood that the p.Pro4255= variant does not have clinical significance. The p.Pro4255= 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, HumanSpliceFinder) 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	-0.85
CADD	Benign	2.5
DANN	Benign	0.69

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: rs62038811; hg19: chr16-2139875;