chr16-2091775-T-TCCC

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.11537+3_11537+5dupGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0076 in 1,609,866 control chromosomes in the GnomAD database, including 115 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0077 ( 109 hom. )

Consequence

PKD1
NM_001009944.3 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.33

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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

PKD1-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 16-2091775-T-TCCC is Benign according to our data. Variant chr16-2091775-T-TCCC is described in ClinVar as [Likely_benign]. Clinvar id is 256903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00644 (979/151994) while in subpopulation SAS AF= 0.0284 (137/4820). AF 95% confidence interval is 0.0245. There are 6 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 979 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.11537+3_11537+5dupGGG		splice_region_variant, intron_variant	Intron 41 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.11537+5_11537+6insGGG		splice_region_variant, intron_variant	Intron 41 of 45	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00643

AC:

977

AN:

151876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.000581

Gnomad SAS

AF:

0.0280

Gnomad FIN

AF:

0.00302

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00899

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0101

AC:

2360

AN:

233058

Hom.:

AF XY:

0.0117

AC XY:

1498

AN XY:

128052

show subpopulations

Gnomad AFR exome

AF:

0.00103

Gnomad AMR exome

AF:

0.00546

Gnomad ASJ exome

AF:

0.0159

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.0293

Gnomad FIN exome

AF:

0.00491

Gnomad NFE exome

AF:

0.00944

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.00772

AC:

11256

AN:

1457872

Hom.:

109

Cov.:

AF XY:

0.00858

AC XY:

6222

AN XY:

725128

show subpopulations

Gnomad4 AFR exome

AF:

0.00135

Gnomad4 AMR exome

AF:

0.00546

Gnomad4 ASJ exome

AF:

0.0175

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0287

Gnomad4 FIN exome

AF:

0.00598

Gnomad4 NFE exome

AF:

0.00626

Gnomad4 OTH exome

AF:

0.00962

GnomAD4 genome

AF:

0.00644

AC:

979

AN:

151994

Hom.:

Cov.:

AF XY:

0.00649

AC XY:

482

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00109

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.000583

Gnomad4 SAS

AF:

0.0284

Gnomad4 FIN

AF:

0.00302

Gnomad4 NFE

AF:

0.00899

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00713

Hom.:

Bravo

AF:

0.00567

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 27, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19686598, 31384335, 10862097) -

Oct 11, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4, BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type

Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 c.11537+3_11537+5dup variant was identified in 9 of 464 proband chromosomes (frequency: 0.02) from individuals or families with ADPKD, and was not identified in 500 control chromosomes from healthy individuals (Stekrova 2009, Bataille 2011, Reed 2008, Rossetti 2002, Vouk 2006,). The variant was also identified in dbSNP (ID: rs201204878) and ADPKD Mutation Database (classified as likely neutral).This variant was identified in the 1000 Genomes Project in 47 of 5000 chromosomes (frequency: 0.009), NHLBI GO Exome Sequencing Project in 72 of 8226 European American and in 13 of 4246 African American alleles. The variant was also identified in Exome Aggregation Consortium database (March 14, 2016) in 1188 (22 homozygous) of 98342 chromosomes (freq. 0.012) in the following populations: European in 606 of 54618 chromosomes (freq. 0.01), South Asian in 448 of 14506 chromosomes (freq. 0.03), Latino in 76 of 9570 chromosomes (freq. 0.008), Finnish in 32 of 4286 chromosomes (freq. 0.007), African in 10 of 7240 chromosomes (freq. 0.001), East Asian in 1 of 7496 chromosomes (freq. 0.0001) and Other in 15 of 626 chromosomes (freq. 0.02), increasing the likelihood this could be a low frequency benign variant. In addition, the variant was identified with a co-occurring pathogenic PKD1 variant in our lab (p.Ala3571_Val3572del), increasing the likelihood that the c.11537+3_11537+5dup variant does not have clinical significance. The c.11537+3_11537+5dup variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this information is not predictive enough to assume pathogenicity. Population study by Vouk (2006) suggests the variant possibly influences splicing of intron 41, however segregation analysis was not performed due to lack of samples from the family. The case study of the family without history of PKD by Reed (2008) predicted poor match between the variant sequence and consensus splice site with evidence for anticipation, considered to be weak. One population study classified the variant as likely silent (Stekrova 2009) while two other population studies classified the variant as polymorphism (Bataille 2011, Rossetti 2002). 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

Splicing

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