rs550769703

chr16-2116900-G-A

Variant summary

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

The NM_001009944.3(PKD1):c.1539C>T(p.Pro513=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00598 in 1,525,452 control chromosomes in the GnomAD database, including 860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P513?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.012 (109 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (751 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.46

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=-0.93).
• BP6: Variant 16-2116900-G-A is Benign according to our data. Variant chr16-2116900-G-A is described in ClinVar as [Benign]. Clinvar id is 256925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2116900-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.1539C>T	p.Pro513=	synonymous_variant	7/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.1539C>T	p.Pro513=	synonymous_variant	7/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1781 AN: 152226 Hom.: 107 Cov.: 33

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0380 AC: 4948 AN: 130094 Hom.: 570 AF XY: 0.0278 AC XY: 1965 AN XY: 70724

Gnomad AFR exome AF: 0.00297

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000476

Gnomad SAS exome AF: 0.000178

Gnomad FIN exome AF: 0.000559

Gnomad NFE exome AF: 0.000205

Gnomad OTH exome AF: 0.0292

GnomAD4 exome AF: 0.00534 AC: 7332 AN: 1373108 Hom.: 751 Cov.: 29 AF XY: 0.00455 AC XY: 3090 AN XY: 679226

Gnomad4 AFR exome AF: 0.00196

Gnomad4 AMR exome AF: 0.183

Gnomad4 ASJ exome AF: 0.0000399

Gnomad4 EAS exome AF: 0.00147

Gnomad4 SAS exome AF: 0.000188

Gnomad4 FIN exome AF: 0.00100

Gnomad4 NFE exome AF: 0.000187

Gnomad4 OTH exome AF: 0.00506

GnomAD4 genome AF: 0.0117 AC: 1790 AN: 152344 Hom.: 109 Cov.: 33 AF XY: 0.0122 AC XY: 908 AN XY: 74494

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00679 Hom.: 13

Bravo AF: 0.0217

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 27, 2020

- -

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.Pro513= variant was identified in 1 of 460 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Rossetti 2012). The variant was also identified in dbSNP (ID: rs550769703) as “With Benign allele”, ClinVar (classified as benign by Prevention Genetics), ADPKD Mutation Database (likely neutral). This variant was identified in the 1000 Genomes Project in 110 of 5000 chromosomes (frequency: 0.022), the Genome Aggregation Database (beta, October 19th 2016) in 5209 (593 homozygous) of 130176 chromosomes (freq. 0.04), the Exome Aggregation Consortium database (August 8th 2016) in 23 (1 homozygous) of 11406 chromosomes (freq. 0.002) in the following populations: Latino in 17 of 158 chromosomes (freq. 0.1), European in 5 of 3112 chromosomes (freq. 0.002), South Asian in 1 of 7474 chromosomes (freq. 0.0001), but was not seen in African, Finnish, East Asian and Other populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was not found in Clinvitae, GeneInsight COGR, MutDB, PKD1-LOVD or PKD1-LOVD 3.0 databases. The p.Pro513Pro 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 30, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.049
Dann	Benign	0.90

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: rs550769703; hg19: chr16-2166901;