chr16-2104523-G-A

Position:

chr16-2104523-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBP6_ModerateBP7BS2_Supporting

The NM_001009944.3(PKD1):c.8136C>T(p.Ile2712=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,557,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.589

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 16-2104523-G-A is Benign according to our data. Variant chr16-2104523-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 448013.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2104523-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.589 with no splicing effect.

BS2

High AC in GnomAd4 at 17 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.8136C>T	p.Ile2712=	synonymous_variant	22/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.8136C>T	p.Ile2712=	synonymous_variant	22/46	1	NM_001009944.3	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.000113

AC:

AN:

149974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000497

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000201

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000190

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000237

AC:

AN:

151988

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

81962

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000677

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000424

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.000462

GnomAD4 exome

AF:

0.000219

AC:

308

AN:

1407800

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

144

AN XY:

697830

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000577

Gnomad4 SAS exome

AF:

0.0000862

Gnomad4 FIN exome

AF:

0.0000635

Gnomad4 NFE exome

AF:

0.000217

Gnomad4 OTH exome

AF:

0.000292

GnomAD4 genome

AF:

0.000113

AC:

AN:

150092

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

73286

show subpopulations

Gnomad4 AFR

AF:

0.0000495

Gnomad4 AMR

AF:

0.000132

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000201

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000190

Gnomad4 NFE

AF:

0.000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000234

Hom.:

Bravo

AF:

0.000196

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 30, 2016

- -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ile2712= variant was not identified in the literature, nor was it identified in GeneInsight COGR, ClinVar, Clinvitae, MutDB, PKD1-LOVD, or PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs754894798) as â€šÃ„ÃºN/Aâ€šÃ„Ã¹, ADPKD Mutation Database (classified as likely neutral), the genome Aggregation Database (beta, October 19th 2016) in 37 of 176006 chromosomes (freq. 0.0002), the Exome Aggregation Consortium database (August 8th 2016) in 4 of 17182 chromosomes (freq. 0.0002) in the following populations: European in 3 of 6330 chromosomes (freq. 0.0005), Latino in 1 of 516 chromosomes (freq. 0.002), but was not seen in African, Asian, Finnish and Other populations. The p.Ile2712= 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, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.80

DANN

Benign

0.80

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