chr16-2090293-C-T

Position:

chr16-2090293-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.12436G>A(p.Val4146Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,609,992 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 34)

Exomes 𝑓: 0.0038 ( 28 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.77

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010210127).

BP6

Variant 16-2090293-C-T is Benign according to our data. Variant chr16-2090293-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2090293-C-T is described in Lovd as [Benign]. Variant chr16-2090293-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00384 (5592/1457686) while in subpopulation MID AF= 0.0175 (101/5760). AF 95% confidence interval is 0.0148. There are 28 homozygotes in gnomad4_exome. There are 2963 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 501 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.12436G>A	p.Val4146Ile	missense_variant	45/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.12436G>A	p.Val4146Ile	missense_variant	45/46	1	NM_001009944.3	ENSP00000262304.4	P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.12433G>A	p.Val4145Ile	missense_variant	45/46	1		ENSP00000399501.1	P98161-3
PKD1	ENST00000472577.1 linkuse as main transcript	n.464G>A		non_coding_transcript_exon_variant	2/3	2
MIR1225	ENST00000408729.1 linkuse as main transcript	n.-9G>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.00329

AC:

501

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00641

Gnomad FIN

AF:

0.00216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00547

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00439

AC:

1076

AN:

244946

Hom.:

AF XY:

0.00484

AC XY:

645

AN XY:

133308

show subpopulations

Gnomad AFR exome

AF:

0.000504

Gnomad AMR exome

AF:

0.00291

Gnomad ASJ exome

AF:

0.00287

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00857

Gnomad FIN exome

AF:

0.00442

Gnomad NFE exome

AF:

0.00498

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00384

AC:

5592

AN:

1457686

Hom.:

Cov.:

AF XY:

0.00409

AC XY:

2963

AN XY:

724654

show subpopulations

Gnomad4 AFR exome

AF:

0.000689

Gnomad4 AMR exome

AF:

0.00283

Gnomad4 ASJ exome

AF:

0.00215

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00834

Gnomad4 FIN exome

AF:

0.00527

Gnomad4 NFE exome

AF:

0.00363

Gnomad4 OTH exome

AF:

0.00448

GnomAD4 genome

AF:

0.00329

AC:

501

AN:

152306

Hom.:

Cov.:

AF XY:

0.00290

AC XY:

216

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00642

Gnomad4 FIN

AF:

0.00216

Gnomad4 NFE

AF:

0.00547

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00474

Hom.:

Bravo

AF:

0.00276

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000911

AC:

ESP6500EA

AF:

0.00431

AC:

ExAC

AF:

0.00470

AC:

569

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00587

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PKD1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2021	This variant is associated with the following publications: (PMID: 22383692, 10200984, 27843768, 27499327, 27401137, 11967008, 31488014) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

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

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2017	- -

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.Val4146Ile variant was identified in 8 of 1080 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD (Badenas 1999, Rossetti 2012, Rossetti 2002, Stekrova 2009). The variant was also identified in the following databases: dbSNP (ID: rs148478410) as â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, ClinVar (1x, as likely benign by Prevention Genetics), LOVD 3.0 (1x, with unknown effect, 1x as "Probably does not affect function"), ADPKD Mutation Database (as likely neutral). The variant was not identified in the PKD1-LOVD database. The variant was identified in control databases in 1211 of 271698 (5 homozygous) chromosomes at a frequency of 0.004457 in the following populations: African in 11 of 23782 chromosomes (freq. 0.00046), other in 41 of 6358 chromosomes (freq. 0.0064), Latino in 102 of 34238 chromosomes (freq. 0.003), European in 644 of 12418 (2 homozygous) chromosomes (freq. 0.005), Ashkenazi Jewish in 30 of 9890 chromosomes (freq. 0.003), East Asian in 1 of 18826 chromosomes (freq. 0.00005), Finnish in 117 of 25656 chromosomes (freq. 0.0045), and South Asian in 265 of 30530 (3 homozygous) chromosomes (freq. 0.0086), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). A co-occurring pathogenic PKD1 variant (c.7864-1G>T) was identified in 1 individual with ADPKD in our laboratory, increasing the likelihood that p.Val4146Ile variant does not have clinical significance. The p.Val4146 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The 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 greater than 10% difference in splicing. However, this information is not predictive enough to assume 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

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.76

N;N

REVEL

Benign

0.072

Sift

Benign

0.16

T;T

Sift4G

Uncertain

0.034

D;D

Polyphen

0.97

D;D

Vest4

0.81

MVP

0.78

ClinPred

0.018

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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