rs11643513

Positions:

chr16-2117969-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.1023C>T(p.Ala341Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0432 in 1,538,560 control chromosomes in the GnomAD database, including 1,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 178 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1377 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.11

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:

PKD1 (HGNC:):

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=-0.89).

BP6

Variant 16-2117969-G-A is Benign according to our data. Variant chr16-2117969-G-A is described in ClinVar as [Benign]. Clinvar id is 256887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2117969-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.11 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0812 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.1023C>T	p.Ala341Ala	synonymous_variant	5/46	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.1023C>T	p.Ala341Ala	synonymous_variant	5/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0385

AC:

5860

AN:

152132

Hom.:

179

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00898

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0852

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0128

Gnomad FIN

AF:

0.0522

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0498

Gnomad OTH

AF:

0.0353

GnomAD3 exomes

AF:

0.0493

AC:

6493

AN:

131760

Hom.:

313

AF XY:

0.0438

AC XY:

3134

AN XY:

71590

show subpopulations

Gnomad AFR exome

AF:

0.00891

Gnomad AMR exome

AF:

0.124

Gnomad ASJ exome

AF:

0.0247

Gnomad EAS exome

AF:

0.000285

Gnomad SAS exome

AF:

0.0150

Gnomad FIN exome

AF:

0.0577

Gnomad NFE exome

AF:

0.0467

Gnomad OTH exome

AF:

0.0477

GnomAD4 exome

AF:

0.0437

AC:

60616

AN:

1386310

Hom.:

1377

Cov.:

AF XY:

0.0429

AC XY:

29595

AN XY:

690410

show subpopulations

Gnomad4 AFR exome

AF:

0.00682

Gnomad4 AMR exome

AF:

0.123

Gnomad4 ASJ exome

AF:

0.0238

Gnomad4 EAS exome

AF:

0.000237

Gnomad4 SAS exome

AF:

0.0145

Gnomad4 FIN exome

AF:

0.0584

Gnomad4 NFE exome

AF:

0.0461

Gnomad4 OTH exome

AF:

0.0357

GnomAD4 genome

AF:

0.0385

AC:

5860

AN:

152250

Hom.:

178

Cov.:

AF XY:

0.0389

AC XY:

2896

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00895

Gnomad4 AMR

AF:

0.0850

Gnomad4 ASJ

AF:

0.0242

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.0130

Gnomad4 FIN

AF:

0.0522

Gnomad4 NFE

AF:

0.0499

Gnomad4 OTH

AF:

0.0350

Alfa

AF:

0.0453

Hom.:

Bravo

AF:

0.0394

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 11, 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.Ala341Ala variant was identified in 36 of 1504 proband chromosomes (frequency: 0.024) from French, Australian, Dutch, British, and American individuals or families with ADPKD (Bataille 22008521, McCluskey 2002, Peters 2001, Rossetti 2001, Tan 2009, Rossetti 2012). The variant was identified in dbSNP (ID: rs11643513) as â€šÃ„ÃºNAâ€šÃ„Ã¹, ADPKD Mutation Database (classification likely neutral), but was not in Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was identified in the 1000 Genomes Project in 130 of 5000 chromosomes (frequency: 0.026), HAPMAP populations: AMR in 66 of 694 chromosomes (frequency: 0.0951) and EUR in 53 of 1006 chromosomes (frequency: 0.0527)/-SAS in 9 or 978 chromosomes (frequency: 0.0092), and in the Exome Aggregation Consortium database (March 14, 2016) in all populations except East Asian: European (Finnish) in 2 of 8 chromosomes (frequency: 0.25), Latino in 18 of 154 chromosomes (frequency: 0.1169), Other in 6 of 120 chromosomes (frequency: 0.05), European (Non-Finnish) in 132 of 2930 chromosomes (frequency: 0.0461), South Asian in 109 of 6226 chromosomes (frequency: 0.0174) and African in 5 of 436 chromosomes (frequency: 0.0115), increasing the likelihood this could be a low frequency benign variant. However we are not able to rule out that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala341Ala 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. The variant occurs outside of the splicing consensus sequence and 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. -

Autosomal dominant polycystic kidney disease

Benign:1

Benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.2

DANN

Benign

0.73

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