rs2549677

Positions:

chr16-2112360-A-G

Variant summary

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

The NM_001009944.3(PKD1):c.3275T>C(p.Met1092Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0875 in 1,514,852 control chromosomes in the GnomAD database, including 13,074 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.20 ( 5154 hom., cov: 33)

Exomes 𝑓: 0.075 ( 7920 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.85

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:

(HGNC:):

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=0.020166844).

BP6

Variant 16-2112360-A-G is Benign according to our data. Variant chr16-2112360-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 256947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2112360-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.3275T>C	p.Met1092Thr	missense_variant	14/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.3275T>C	p.Met1092Thr	missense_variant	14/46	1	NM_001009944.3	P5	P98161-1
	ENST00000568795.1 linkuse as main transcript	n.26A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.197

AC:

29974

AN:

152056

Hom.:

5135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.462

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.0758

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.0991

Gnomad OTH

AF:

0.192

GnomAD3 exomes

AF:

0.0721

AC:

15410

AN:

213684

Hom.:

1527

AF XY:

0.0656

AC XY:

7765

AN XY:

118316

show subpopulations

Gnomad AFR exome

AF:

0.397

Gnomad AMR exome

AF:

0.0671

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.0000560

Gnomad SAS exome

AF:

0.0204

Gnomad FIN exome

AF:

0.0399

Gnomad NFE exome

AF:

0.0674

Gnomad OTH exome

AF:

0.0886

GnomAD4 exome

AF:

0.0752

AC:

102537

AN:

1362680

Hom.:

7920

Cov.:

AF XY:

0.0729

AC XY:

49520

AN XY:

678960

show subpopulations

Gnomad4 AFR exome

AF:

0.434

Gnomad4 AMR exome

AF:

0.0757

Gnomad4 ASJ exome

AF:

0.125

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0259

Gnomad4 FIN exome

AF:

0.0619

Gnomad4 NFE exome

AF:

0.0705

Gnomad4 OTH exome

AF:

0.0967

GnomAD4 genome

AF:

0.197

AC:

30036

AN:

152172

Hom.:

5154

Cov.:

AF XY:

0.190

AC XY:

14124

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.462

Gnomad4 AMR

AF:

0.136

Gnomad4 ASJ

AF:

0.159

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0280

Gnomad4 FIN

AF:

0.0758

Gnomad4 NFE

AF:

0.0991

Gnomad4 OTH

AF:

0.190

Alfa

AF:

0.148

Hom.:

515

Bravo

AF:

0.217

ExAC

AF:

0.0712

AC:

8153

ClinVar

Significance: Benign/Likely 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	Jun 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 07, 2020	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2019	This variant is associated with the following publications: (PMID: 22608885) -

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.3275T>C, p.Met1092Thr variant was identified in 7.5% of 6086 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

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

0.037

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.67

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0020

LIST_S2

Benign

0.21

T;T

MetaRNN

Benign

0.020

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-2.7

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.41

PROVEAN

Benign

2.5

N;N

REVEL

Benign

0.15

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;B

Vest4

0.032

ClinPred

0.0033

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.044

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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