rs371762181

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BP6

The NM_001009944.3(PKD1):c.10240G>A(p.Gly3414Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 1,602,250 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00071 ( 1 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.91

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant polycystic kidney disease
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
polycystic kidney disease 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
autosomal recessive polycystic kidney disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Caroli disease
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

PKD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_001009944.3

BP6

Variant 16-2097484-C-T is Benign according to our data. Variant chr16-2097484-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 433999.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.10240G>A	p.Gly3414Ser	missense	Exon 33 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.10237G>A	p.Gly3413Ser	missense	Exon 33 of 46	NP_000287.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PKD1	ENST00000262304.9	TSL:1 MANE Select	c.10240G>A	p.Gly3414Ser	missense	Exon 33 of 46	ENSP00000262304.4
PKD1	ENST00000423118.5	TSL:1	c.10237G>A	p.Gly3413Ser	missense	Exon 33 of 46	ENSP00000399501.1
PKD1	ENST00000487932.5	TSL:5	n.*1433G>A		non_coding_transcript_exon	Exon 20 of 30	ENSP00000457132.1

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000394

AC:

AN:

238586

AF XY:

0.000458

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000681

Gnomad NFE exome

AF:

0.000729

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000714

AC:

1035

AN:

1449912

Hom.:

Cov.:

AF XY:

0.000702

AC XY:

507

AN XY:

721848

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000598

AC:

AN:

33428

American (AMR)

AF:

0.0000447

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000325

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.0000464

AC:

AN:

43096

Middle Eastern (MID)

AF:

0.000423

AC:

AN:

4728

European-Non Finnish (NFE)

AF:

0.000865

AC:

962

AN:

1111770

Other (OTH)

AF:

0.000581

AC:

AN:

60194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000394

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41578

American (AMR)

AF:

0.000131

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000287

Hom.:

Bravo

AF:

0.000450

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000467

AC:

ExAC

AF:

0.000364

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not specified (1)

Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.13

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.46

M_CAP

Benign

0.0096

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.3

PhyloP100

2.9

PrimateAI

Benign

0.38

PROVEAN

Benign

2.0

REVEL

Benign

0.11

Sift

Benign

0.94

Sift4G

Benign

1.0

Polyphen

0.024

Vest4

0.15

MVP

0.38

ClinPred

0.0091

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.013

gMVP

0.11

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.30

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over