16-2109713-C-T

Position:

chr16-2109713-C-T

Variant summary

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

The NM_001009944.3(PKD1):c.5454G>A(p.Ala1818=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00759 in 1,602,118 control chromosomes in the GnomAD database, including 776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 421 hom., cov: 33)

Exomes 𝑓: 0.0043 ( 355 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -5.37

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=-0.95).

BP6

Variant 16-2109713-C-T is Benign according to our data. Variant chr16-2109713-C-T is described in ClinVar as [Benign]. Clinvar id is 256978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109713-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-5.37 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.5454G>A	p.Ala1818=	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.5454G>A	p.Ala1818=	synonymous_variant	15/46	1	NM_001009944.3	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0390

AC:

5934

AN:

152180

Hom.:

418

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0172

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.0336

GnomAD3 exomes

AF:

0.00987

AC:

2216

AN:

224612

Hom.:

122

AF XY:

0.00731

AC XY:

900

AN XY:

123050

show subpopulations

Gnomad AFR exome

AF:

0.137

Gnomad AMR exome

AF:

0.00807

Gnomad ASJ exome

AF:

0.00630

Gnomad EAS exome

AF:

0.000238

Gnomad SAS exome

AF:

0.0000691

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000628

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.00428

AC:

6202

AN:

1449820

Hom.:

355

Cov.:

AF XY:

0.00369

AC XY:

2657

AN XY:

720454

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.00915

Gnomad4 ASJ exome

AF:

0.00803

Gnomad4 EAS exome

AF:

0.000204

Gnomad4 SAS exome

AF:

0.000153

Gnomad4 FIN exome

AF:

0.0000390

Gnomad4 NFE exome

AF:

0.000366

Gnomad4 OTH exome

AF:

0.0102

GnomAD4 genome

AF:

0.0391

AC:

5952

AN:

152298

Hom.:

421

Cov.:

AF XY:

0.0378

AC XY:

2817

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.133

Gnomad4 AMR

AF:

0.0172

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.0332

Alfa

AF:

0.00348

Hom.:

Bravo

AF:

0.0446

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2019	This variant is associated with the following publications: (PMID: 22383692) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 02, 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.Ala1818Ala was identified in 1 of 460 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD, and was not identified in 68 control chromosomes from healthy individuals (Rossetti 2012). The variant is listed in the dbSNP database (ID#: rs143916489) The variant was also identified in the 1000 Genomes Project in 236 of 5011 chromosomes (frequency: 0.0471) and in the NHLBI GO Exome Sequencing Project in 9 of 8516 European American (frequency: 0.001) and 554 of 4312 African American (frequency: 0.128) alleles. Furthermore, the variant is listed in the Exome Aggregation Consortium database (March 14, 2016) in 1081 of 49564 chromosomes (frequency: 0.021) including in the African population 969 (61 homozygous) of 4458 chromosomes (freq. 0.2174), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. We cannot be certain that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant is also identified in GeneInsight COGR and listed in the ADPKD Mutation Database 5x as likely neutral. The p.Ala1818Ala 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, 4 of 5 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

-0.95

CADD

Benign

0.28

DANN

Benign

0.62

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