rs148727945

chr16-2112452-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001009944.3(PKD1):c.3183G>A(p.Glu1061=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,588,386 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (12 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.407

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 16-2112452-C-T is Benign according to our data. Variant chr16-2112452-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2112452-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.407 with no splicing effect.
• BS2: High AC in GnomAd at 244 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.3183G>A	p.Glu1061=	synonymous_variant	14/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.3183G>A	p.Glu1061=	synonymous_variant	14/46	1	NM_001009944.3	P5
	ENST00000568795.1	n.118C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00268

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00153 AC: 291 AN: 190260 Hom.: 1 AF XY: 0.00152 AC XY: 159 AN XY: 104800

Gnomad AFR exome AF: 0.000403

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00263

Gnomad OTH exome AF: 0.00236

GnomAD4 exome AF: 0.00282 AC: 4048 AN: 1436064 Hom.: 12 Cov.: 32 AF XY: 0.00268 AC XY: 1911 AN XY: 714122

Gnomad4 AFR exome AF: 0.000603

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.000430

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.00146 AC XY: 109 AN XY: 74484

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00268

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00226 Hom.: 0

Bravo AF: 0.00167

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2019	- -
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	GeneDx	Oct 22, 2020	- -

Polycystic kidney disease, adult type Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 23, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The PKD1 p.Glu1061Glu variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from individuals or families with clinical features of polycystic renal disease (Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs148727945) as “NA”, in the ADPKD Mutation Database (classification “likely neutral”), but was not in Clinvitae, ClinVar , GeneInsight COGR, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was identified in the 1000 Genomes Project in 5 of 5000 chromosomes (frequency: 0.001), HAPMAP-EUR in 5 of 1006 chromosomes (frequency: 0.005), NHLBI GO Exome Sequencing Project in 10 of 4570 European American alleles and in 2 of 2590 African American alleles, and in the Exome Aggregation Consortium database (March 14, 2016) in 84 of 43768 alleles, specifically in 68 of 22746 alleles (1 homozygous, frequency: 0.0030) from a population of European (Non-Finnish) individuals, in 14 of 3386 alleles (frequency: 0.0041) from a Latino population, and in 2 of 2432 alleles (frequency: 0.0008) from an African population. The variant was not seen in East Asian, South Asian, or European (Finnish) populations. The p.Glu1061Glu 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. This variant was identified in our laboratory in one individual with ADPKD and a co-occurring pathogenic variant in PKD1 (c.160_166dup, p.Leu56ProfsX60), increasing the likelihood this variant does not have clinical significance. 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	-0.76
Cadd	Benign	4.9
Dann	Benign	0.74

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: rs148727945; hg19: chr16-2162453;