chr16-2102864-C-G

Position:

chr16-2102864-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000262304.9(PKD1):c.8898G>C(p.Glu2966Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,594,798 control chromosomes in the GnomAD database, including 1,046 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.052 ( 547 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 499 hom. )

Consequence

PKD1
ENST00000262304.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.628

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002373308).

BP6

Variant 16-2102864-C-G is Benign according to our data. Variant chr16-2102864-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 257030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2102864-C-G is described in Lovd as [Benign]. Variant chr16-2102864-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 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.8898G>C	p.Glu2966Asp	missense_variant	24/46	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.8898G>C	p.Glu2966Asp	missense_variant	24/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0517

AC:

7124

AN:

137814

Hom.:

547

Cov.:

show subpopulations

Gnomad AFR

AF:

0.179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0240

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00119

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0145

Gnomad NFE

AF:

0.000503

Gnomad OTH

AF:

0.0402

GnomAD3 exomes

AF:

0.0124

AC:

3076

AN:

248986

Hom.:

233

AF XY:

0.00895

AC XY:

1210

AN XY:

135182

show subpopulations

Gnomad AFR exome

AF:

0.166

Gnomad AMR exome

AF:

0.00903

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000428

Gnomad OTH exome

AF:

0.00427

GnomAD4 exome

AF:

0.00474

AC:

6900

AN:

1456864

Hom.:

499

Cov.:

AF XY:

0.00395

AC XY:

2859

AN XY:

724698

show subpopulations

Gnomad4 AFR exome

AF:

0.163

Gnomad4 AMR exome

AF:

0.0104

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000419

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000247

Gnomad4 OTH exome

AF:

0.0110

GnomAD4 genome

AF:

0.0517

AC:

7133

AN:

137934

Hom.:

547

Cov.:

AF XY:

0.0495

AC XY:

3342

AN XY:

67574

show subpopulations

Gnomad4 AFR

AF:

0.178

Gnomad4 AMR

AF:

0.0240

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000955

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000503

Gnomad4 OTH

AF:

0.0397

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.0537

ESP6500AA

AF:

0.156

AC:

686

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.0152

AC:

1837

EpiCase

AF:

0.000164

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2019	This variant is associated with the following publications: (PMID: 11115377, 27499327, 22008521, 27894351, 27884173, 11216660, 20981092) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Dec 17, 2019

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Glu2966Asp variant was identified in 3 of 548 proband chromosomes (frequency: 0.005) as a polymorphism from individuals or families with ADPKD, but it was not identified in 442 control chromosomes from healthy individuals (Bataille 2011, Rossetti 2001, Garcia-Gonzalez 2007). In addition the PKD1 p.Glu2966Asp variant was reported co-occurring with 2 pathogenic PKD1 variants (1470A>G, Y420C and 4262C>T, R1351W) in a proband (Garcia-Gonzalez_2007). The variant was identified in dbSNP (ID: rs13337123) as â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, Clinvitae (as benign), ClinVar (as benign by PreventionGenetics), MutDB, ADPKD Mutation Database (as likely neutral), and PKD1-LOVD 3.0 (unclassified). This variant was also identified in the 1000 Genomes Project in 254 of 5008 chromosomes (frequency: 0.0507) the NHLBI GO Exome Sequencing Project in 4 of 8584 European American alleles (freq: 0.0004) and in 686 of 4388 African American alleles (freq: 0.156), the genome Aggregation Database (beta, October 19th 2016) in 3345 (258 homozygous) of 250832 chromosomes (freq. 0.013), the Exome Aggregation Consortium database (August 8th 2016) in 1829 (149 homozygous) of 119830 chromosomes (freq. 0.015) in the following populations: African in 1716 of 10204 chromosomes (freq. 0.17), Latino in 82 of 11540 chromosomes (freq. 0.007), other in 5 of 888 chromosomes (freq. 0.0056), South Asian in 6 of 16504 chromosomes (freq. 0.00036), and European in 20 of 65458 chromosomes (freq. 0.00030), but was not seen in East Asian and Finnish populations. The variant was identified by our laboratory in 2 individuals with ADPKD with a co-occurring pathogenic PKD1 variant (c.3489delC, p.Phe1163Leufsx8 and c.2494dupC, p.Arg832ProfsX40), increasing the likelihood that the p.Glu2966Asp variant does not have clinical significance. The PKD1 p.Glu2966Asp variant was not identified in GeneInsight COGR , PKD1-LOVD and HAPMAP databases. 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. The p.Glu2966 residue is not conserved in mammals and other organism, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Likely 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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

2.6

DANN

Benign

0.70

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.45

T;T

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

0.99

P;P

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.53

N;N

REVEL

Benign

0.029

Sift

Benign

0.29

T;T

Sift4G

Benign

0.099

T;T

Polyphen

0.0090

B;B

Vest4

0.043

MutPred

0.38

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

ClinPred

0.00095

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.26

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