rs886038369

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.182C>T(p.Pro61Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,170,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.636

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19904986).

BP6

Variant 16-2135508-G-A is Benign according to our data. Variant chr16-2135508-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2135508-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000603 (91/151034) while in subpopulation NFE AF= 0.00117 (79/67646). AF 95% confidence interval is 0.00096. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PKD1	NM_001009944.3 link	c.182C>T	p.Pro61Leu	missense_variant	Exon 1 of 46	ENST00000262304.9	NP_001009944.3
PKD1	NM_000296.4 link	c.182C>T	p.Pro61Leu	missense_variant	Exon 1 of 46		NP_000287.4
PKD1	XM_047434208.1 link	c.182C>T	p.Pro61Leu	missense_variant	Exon 1 of 48		XP_047290164.1
PKD1	XM_047434209.1 link	c.182C>T	p.Pro61Leu	missense_variant	Exon 1 of 47		XP_047290165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.182C>T	p.Pro61Leu	missense_variant	Exon 1 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1
PKD1	ENST00000423118.5 link	c.182C>T	p.Pro61Leu	missense_variant	Exon 1 of 46	1		ENSP00000399501.1		P98161-3

Frequencies

GnomAD3 genomes

AF:

0.000603

AC:

AN:

151034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000983

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00117

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00111

AC:

1130

AN:

1019046

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

537

AN XY:

479718

show subpopulations

Gnomad4 AFR exome

AF:

0.0000965

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00125

Gnomad4 OTH exome

AF:

0.000688

GnomAD4 genome

AF:

0.000603

AC:

AN:

151034

Hom.:

Cov.:

AF XY:

0.000597

AC XY:

AN XY:

73736

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000983

Gnomad4 NFE

AF:

0.00117

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.000661

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11967008, 18837007, 30792735) -

Mar 02, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.66

T;T

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.080

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.026

D;D

Polyphen

0.92

P;P

Vest4

0.23

MVP

0.67

ClinPred

0.39

GERP RS

2.1

Varity_R

0.091

gMVP

0.33

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