rs189277711

Positions:

chr16-2108021-G-A

Variant summary

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

The NM_001009944.3(PKD1):c.6927C>T(p.Gly2309=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,553,324 control chromosomes in the GnomAD database, including 308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 33)

Exomes 𝑓: 0.018 ( 284 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.39

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=-0.8).

BP6

Variant 16-2108021-G-A is Benign according to our data. Variant chr16-2108021-G-A is described in ClinVar as [Benign]. Clinvar id is 256994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2108021-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.39 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0138 (2097/152288) while in subpopulation NFE AF= 0.0195 (1323/68004). AF 95% confidence interval is 0.0186. There are 24 homozygotes in gnomad4. There are 1040 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2097 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.6927C>T	p.Gly2309=	synonymous_variant	16/46	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.6927C>T	p.Gly2309=	synonymous_variant	16/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

2097

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0101

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0369

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0195

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0131

AC:

2000

AN:

152096

Hom.:

AF XY:

0.0130

AC XY:

1071

AN XY:

82084

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00482

Gnomad ASJ exome

AF:

0.00522

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00675

Gnomad FIN exome

AF:

0.0315

Gnomad NFE exome

AF:

0.0197

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.0184

AC:

25727

AN:

1401036

Hom.:

284

Cov.:

AF XY:

0.0180

AC XY:

12434

AN XY:

691940

show subpopulations

Gnomad4 AFR exome

AF:

0.00292

Gnomad4 AMR exome

AF:

0.00584

Gnomad4 ASJ exome

AF:

0.00503

Gnomad4 EAS exome

AF:

0.0000275

Gnomad4 SAS exome

AF:

0.00704

Gnomad4 FIN exome

AF:

0.0331

Gnomad4 NFE exome

AF:

0.0206

Gnomad4 OTH exome

AF:

0.0145

GnomAD4 genome

AF:

0.0138

AC:

2097

AN:

152288

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1040

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00366

Gnomad4 AMR

AF:

0.0101

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.0369

Gnomad4 NFE

AF:

0.0195

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.0119

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2019	This variant is associated with the following publications: (PMID: 11967008, 11857740, 10854095) -
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

Mar 23, 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.Gly2309Gly variant was identified in 17 of 732 proband chromosomes (frequency: 0.023) from individuals or families with ADPKD or renal disease, and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011, Garcia-Gonzalez 2007, McCluskey 2002, Rossetti 2012). The above studies determined this variant to be classified as a polymorphism based on either it being a synonymous variant, in silico analysis or interspecies conservation. The p.Gly2309Gly variant was identified in the dbSNP (ID: rs189277711) with unknown clinical significance with a minor allele frequency 0.0082 (41 of 5000 chromosomes in 1000 Genome Project). In the NHLBI Exome Sequencing Project, the variant was identified in 119 of 7256 alleles (frequency: 0.0164) in European Americans and 10 of 3486 African Americans (frequency: 0.00286). The variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 214 of 15790 alleles, 5 of which are homozygous (frequency: 0.0135) or 6 of 56 of European (Finnish), 138 of 5652 European (Non-Finnish), 8 of 380 Latino, 7 of 1120 African, 54 of 7844 South Asians, 1 of 168 other alleles and was not found in East Asians. The variant was identified in the ADPKD Mutation Database and classified as likely neutral. The c.6927C>T variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a location change of a cryptic 5â€šÃ„Ã´ splice donor site; this is not very predictive of pathogenicity. The p.Gly2309Gly 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 this variant was identified by our laboratory as co-occurring with pathogenic PKD1 variants in two different families with polycystic kidney disease (PKD1, EXON43, c.11798_11810del, p.Leu3933ArgfsX8 and c.2215C>T, p.Gln739X), increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant meets our 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

-0.80

CADD

Benign

0.34

DANN

Benign

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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