chr16-2106446-G-A

Position:

chr16-2106446-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.7441C>T(p.Leu2481=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,588,648 control chromosomes in the GnomAD database, including 27,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 6287 hom., cov: 33)

Exomes 𝑓: 0.16 ( 21307 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.199

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=-0.85).

BP6

Variant 16-2106446-G-A is Benign according to our data. Variant chr16-2106446-G-A is described in ClinVar as [Benign]. Clinvar id is 257001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2106446-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.199 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 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.7441C>T	p.Leu2481=	synonymous_variant	18/46	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.7441C>T	p.Leu2481=	synonymous_variant	18/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.244

AC:

37139

AN:

152022

Hom.:

6264

Cov.:

show subpopulations

Gnomad AFR

AF:

0.474

Gnomad AMI

AF:

0.134

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.0906

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.242

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.237

GnomAD3 exomes

AF:

0.155

AC:

27935

AN:

180552

Hom.:

3005

AF XY:

0.151

AC XY:

15137

AN XY:

99930

show subpopulations

Gnomad AFR exome

AF:

0.491

Gnomad AMR exome

AF:

0.111

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.0911

Gnomad FIN exome

AF:

0.190

Gnomad NFE exome

AF:

0.163

Gnomad OTH exome

AF:

0.174

GnomAD4 exome

AF:

0.161

AC:

231041

AN:

1436508

Hom.:

21307

Cov.:

AF XY:

0.158

AC XY:

113016

AN XY:

714054

show subpopulations

Gnomad4 AFR exome

AF:

0.487

Gnomad4 AMR exome

AF:

0.117

Gnomad4 ASJ exome

AF:

0.240

Gnomad4 EAS exome

AF:

0.000333

Gnomad4 SAS exome

AF:

0.0923

Gnomad4 FIN exome

AF:

0.182

Gnomad4 NFE exome

AF:

0.160

Gnomad4 OTH exome

AF:

0.175

GnomAD4 genome

AF:

0.245

AC:

37205

AN:

152140

Hom.:

6287

Cov.:

AF XY:

0.241

AC XY:

17909

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.475

Gnomad4 AMR

AF:

0.177

Gnomad4 ASJ

AF:

0.237

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.0900

Gnomad4 FIN

AF:

0.191

Gnomad4 NFE

AF:

0.159

Gnomad4 OTH

AF:

0.235

Alfa

AF:

0.200

Hom.:

808

Bravo

AF:

0.255

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2019	This variant is associated with the following publications: (PMID: 22608885) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 07, 2020

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The c.7441C>T, p.Leu2481Leu variant was identified in 21.44% of 8928 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

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

-0.85

CADD

Benign

1.2

DANN

Benign

0.63

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