rs142575178

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.4872C>T(p.Ile1624=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000367 in 1,612,654 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.77

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 16-2110295-G-A is Benign according to our data. Variant chr16-2110295-G-A is described in ClinVar as [Benign]. Clinvar id is 433964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110295-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00189 (288/152356) while in subpopulation AFR AF= 0.00661 (275/41590). AF 95% confidence interval is 0.00597. There are 2 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 288 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.4872C>T	p.Ile1624=	synonymous_variant	15/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.4872C>T	p.Ile1624=	synonymous_variant	15/46	1	NM_001009944.3	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

288

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00663

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.000526

AC:

131

AN:

249190

Hom.:

AF XY:

0.000450

AC XY:

AN XY:

135408

show subpopulations

Gnomad AFR exome

AF:

0.00798

Gnomad AMR exome

AF:

0.0000868

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000208

AC:

304

AN:

1460298

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

128

AN XY:

726438

show subpopulations

Gnomad4 AFR exome

AF:

0.00822

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.00189

AC:

288

AN:

152356

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

127

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00661

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.00226

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 20, 2019

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ile1624Ile variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD and PKD1-LOVD 3.0 databases nor was it identified in the NHLBI GO Exome Sequencing Project. The variant was identified in the ADPKD Mutation Database as likely neutral. The variant was also identified in dbSNP (ID: rs142575178) as â€šÃ„ÃºNAâ€šÃ„Ã¹, in the 1000 Genomes Project in 14 of 500 chromosomes (frequency: 0.028), in the Exome Aggregation Consortium database (August 8, 2016) in 77 of 118592 chromosomes (frequency: 0.0006) in the following populations: African in 76 of 9904 chromosomes (frequency: 0.008) and European (Non-Finnish) in 1 of 61652 chromosomes (frequency: 0.00002), but was not seen in East Asian, European (Finnish), Latino and South Asian populations. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ile1624Ile 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. -

PKD1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

5.1

DANN

Benign

0.81

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