chr16-2094175-G-A

Position:

chr16-2094175-G-A

Variant summary

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

The ENST00000262304.9(PKD1):c.10535C>T(p.Ala3512Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 1,603,254 control chromosomes in the GnomAD database, including 5,443 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A3512A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.091 ( 736 hom., cov: 33)

Exomes 𝑓: 0.076 ( 4707 hom. )

Consequence

PKD1
ENST00000262304.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.536

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:

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=0.002803743).

BP6

Variant 16-2094175-G-A is Benign according to our data. Variant chr16-2094175-G-A is described in ClinVar as [Benign]. Clinvar id is 256893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2094175-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 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.10535C>T	p.Ala3512Val	missense_variant	35/46	ENST00000262304.9	NP_001009944.3
PKD1-AS1	NR_135175.1 linkuse as main transcript	n.304-546G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.10535C>T	p.Ala3512Val	missense_variant	35/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1
PKD1-AS1	ENST00000563284.3 linkuse as main transcript	n.195-546G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0905

AC:

13762

AN:

152136

Hom.:

735

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0584

Gnomad ASJ

AF:

0.0979

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0433

Gnomad FIN

AF:

0.145

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0774

Gnomad OTH

AF:

0.0735

GnomAD3 exomes

AF:

0.0726

AC:

16961

AN:

233670

Hom.:

763

AF XY:

0.0722

AC XY:

9205

AN XY:

127414

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.0345

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.000278

Gnomad SAS exome

AF:

0.0443

Gnomad FIN exome

AF:

0.144

Gnomad NFE exome

AF:

0.0811

Gnomad OTH exome

AF:

0.0742

GnomAD4 exome

AF:

0.0765

AC:

110966

AN:

1451002

Hom.:

4707

Cov.:

AF XY:

0.0754

AC XY:

54426

AN XY:

721564

show subpopulations

Gnomad4 AFR exome

AF:

0.124

Gnomad4 AMR exome

AF:

0.0361

Gnomad4 ASJ exome

AF:

0.109

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0443

Gnomad4 FIN exome

AF:

0.144

Gnomad4 NFE exome

AF:

0.0781

Gnomad4 OTH exome

AF:

0.0747

GnomAD4 genome

AF:

0.0905

AC:

13779

AN:

152252

Hom.:

736

Cov.:

AF XY:

0.0927

AC XY:

6900

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.129

Gnomad4 AMR

AF:

0.0583

Gnomad4 ASJ

AF:

0.0979

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0429

Gnomad4 FIN

AF:

0.145

Gnomad4 NFE

AF:

0.0774

Gnomad4 OTH

AF:

0.0728

Alfa

AF:

0.0802

Hom.:

600

Bravo

AF:

0.0843

TwinsUK

AF:

0.0836

AC:

310

ALSPAC

AF:

0.0794

AC:

306

ESP6500AA

AF:

0.125

AC:

547

ESP6500EA

AF:

0.0816

AC:

701

ExAC

AF:

0.0728

AC:

8774

Asia WGS

AF:

0.0320

AC:

112

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 22, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2019	- -
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

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The c.10535C>T, p.Ala3512Val variant was identified in 10.09% of 7978 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

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

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.74

DANN

Benign

0.43

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0061

LIST_S2

Benign

0.46

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.13

N;N

REVEL

Benign

0.035

Sift

Benign

1.0

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.23

B;B

Vest4

0.026

ClinPred

0.012

GERP RS

-9.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.018

gMVP

0.22

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