16-2114329-T-G

Position:

chr16-2114329-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001009944.3(PKD1):c.2694A>C(p.Ala898=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,610,450 control chromosomes in the GnomAD database, including 380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 25 hom., cov: 32)

Exomes 𝑓: 0.020 ( 355 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.13

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=-0.92).

BP6

Variant 16-2114329-T-G is Benign according to our data. Variant chr16-2114329-T-G is described in ClinVar as [Benign]. Clinvar id is 256935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2114329-T-G is described in Lovd as [Benign]. Variant chr16-2114329-T-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.13 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2017/152316) while in subpopulation NFE AF= 0.022 (1493/68018). AF 95% confidence interval is 0.021. There are 25 homozygotes in gnomad4. There are 935 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2017 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.2694A>C	p.Ala898=	synonymous_variant	11/46	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.2694A>C	p.Ala898=	synonymous_variant	11/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2017

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00870

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0219

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0130

AC:

3211

AN:

247924

Hom.:

AF XY:

0.0129

AC XY:

1741

AN XY:

134848

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.00681

Gnomad ASJ exome

AF:

0.00322

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00275

Gnomad FIN exome

AF:

0.0164

Gnomad NFE exome

AF:

0.0213

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0205

AC:

29858

AN:

1458134

Hom.:

355

Cov.:

AF XY:

0.0201

AC XY:

14581

AN XY:

725394

show subpopulations

Gnomad4 AFR exome

AF:

0.00341

Gnomad4 AMR exome

AF:

0.00689

Gnomad4 ASJ exome

AF:

0.00299

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00277

Gnomad4 FIN exome

AF:

0.0171

Gnomad4 NFE exome

AF:

0.0243

Gnomad4 OTH exome

AF:

0.0197

GnomAD4 genome

AF:

0.0132

AC:

2017

AN:

152316

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

935

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00366

Gnomad4 AMR

AF:

0.00869

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.0165

Gnomad4 NFE

AF:

0.0220

Gnomad4 OTH

AF:

0.0113

Alfa

AF:

0.0126

Hom.:

Bravo

AF:

0.0122

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0211

EpiControl

AF:

0.0171

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2018	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2019	This variant is associated with the following publications: (PMID: 10364515, 11857740, 17574468, 24374109) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ala898Ala variant was identified in 24 of 1346 proband chromosomes (frequency: 0.02) from individuals or families with ADPKD (Garcia-Gonzalez 2007, McCluskey 2002, Peltola 2005, Rossetti 2002, Rossetti 2012, Tan 2009, Thomas 1999). The variant was identified in dbSNP (ID: rs142357713) as â€šÃ„ÃºN/Aâ€šÃ„Ã¹ and the ADPKD Mutation Database (as likely neutral). This variant was also identified in the 1000 Genomes Project in 33 of 5000 chromosomes (frequency: 0.007), the NHLBI GO Exome Sequencing Project in 188 of 8578 European American and in 16 of 4376 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 1479 (11 homozygous) of 115044 chromosomes (freq. 0.01) in the following populations: European in 1216 of 62988 chromosomes (freq. 0.02), Finnish in 109 of 5876 chromosomes (freq. 0.02), Latino in 61 of 11260 chromosomes (freq. 0.005), South Asian in 45 of 16324 chromosomes (freq. 0.003), African in 39 of 9280 chromosomes (freq. 0.004), Other in 9 of 830 chromosomes (freq. 0.01), increasing the likelihood this could be a low frequency benign variant. However we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala898Ala 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In addition, the variant is classified as a polymorphism by number of population and statistics studies (McCluskey 2002, Peltola 2005, Rossetti 2002, Rossetti 2012, Tan 2009, Thomas 1999). 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

-0.92

CADD

Benign

0.27

DANN

Benign

0.47

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