16-2103693-C-T

Position:

chr16-2103693-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001009944.3(PKD1):c.8364G>A(p.Ser2788=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,609,960 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0021 ( 5 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.74

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 16-2103693-C-T is Benign according to our data. Variant chr16-2103693-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2103693-C-T is described in Lovd as [Benign]. Variant chr16-2103693-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.74 with no splicing effect.

BS2

High AC in GnomAd4 at 197 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.8364G>A	p.Ser2788=	synonymous_variant	23/46	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.8364G>A	p.Ser2788=	synonymous_variant	23/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

197

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000391

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00232

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00111

AC:

269

AN:

243276

Hom.:

AF XY:

0.00117

AC XY:

156

AN XY:

133366

show subpopulations

Gnomad AFR exome

AF:

0.000349

Gnomad AMR exome

AF:

0.000669

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.0000558

Gnomad SAS exome

AF:

0.000786

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.00188

Gnomad OTH exome

AF:

0.00152

GnomAD4 exome

AF:

0.00214

AC:

3127

AN:

1457814

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

1493

AN XY:

725214

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.000627

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.000859

Gnomad4 FIN exome

AF:

0.0000577

Gnomad4 NFE exome

AF:

0.00258

Gnomad4 OTH exome

AF:

0.00218

GnomAD4 genome

AF:

0.00129

AC:

197

AN:

152146

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000392

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00232

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00179

Hom.:

Bravo

AF:

0.00138

EpiCase

AF:

0.00267

EpiControl

AF:

0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 13, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	PKD1: BP4, BP7, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely 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 08, 2019

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Ser2788= variant was identified in 1 of 460 proband chromosomes (freq 0.002) from individuals or families with PKD (Rossetti 2012). The variant was also identified in dbSNP (ID: rs145176597) as â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, in Clinvitae and ClinVar (as likely benign by PreventionGenetics), ADPKD Mutation Database (as likely neutral), and PKD1-LOVD 3.0 (2x, unclassified with the probability of no functional affect), the 1000 Genomes Project in 4 of 5008 chromosomes (freq 0.0008), the NHLBI GO Exome Sequencing Project in 20 of 8446 European American alleles (freq 0.0023) and 2 in 4306 African American alleles (freq 0.00045), the genome Aggregation Database (beta, October 19th 2016) in 286 (1 homozygous) of 271612 chromosomes (freq. 0.001), the Exome Aggregation Consortium database (August 8th 2016) in 108 (1 homozygous) of 113342 chromosomes (freq. 0.001) in the following populations: European in 84 of 61652 chromosomes (freq. 0.001), South Asian in 13 of 16422 chromosomes (freq. 0.0008), Latino in 8 of 11282 chromosomes (freq. 0.0007), African in 2 of 8270 chromosomes (freq. 0.00024), and East Asian in 1 of 8378 chromosomes (freq. 0.0001), but was not seen in Finnish and other populations, increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. This variant was not identified in GeneInsight-COGR, MutDB, and PKD1-LOVD databases. The p.Ser2788= 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 summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.4

DANN

Benign

0.94

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