rs550769703

Positions:

chr16-2116900-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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 (★★).

Frequency

Genomes: 𝑓 0.012 ( 109 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 751 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -4.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.1539C>T	p.Pro513=	synonymous_variant	7/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.1539C>T	p.Pro513=	synonymous_variant	7/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1781

AN:

152226

Hom.:

107

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00455

AC XY:

3090

AN XY:

679226

show subpopulations

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.:

AF XY:

0.0122

AC XY:

908

AN XY:

74494

show subpopulations

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.:

Bravo

AF:

0.0217

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

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 â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, 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. -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over