chr16-2099651-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001009944.3(PKD1):c.10043G>A(p.Arg3348Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000594 in 1,591,192 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3348W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 1 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 5.44

Publications

5 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: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056121916).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000606 (872/1438860) while in subpopulation NFE AF = 0.000739 (820/1109014). AF 95% confidence interval is 0.000697. There are 1 homozygotes in GnomAdExome4. There are 420 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.10043G>A	p.Arg3348Gln	missense	Exon 30 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.10043G>A	p.Arg3348Gln	missense	Exon 30 of 46	NP_000287.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PKD1	ENST00000262304.9	TSL:1 MANE Select	c.10043G>A	p.Arg3348Gln	missense	Exon 30 of 46	ENSP00000262304.4
PKD1	ENST00000423118.5	TSL:1	c.10043G>A	p.Arg3348Gln	missense	Exon 30 of 46	ENSP00000399501.1
PKD1	ENST00000480227.5	TSL:1	n.1780G>A		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000305

AC:

AN:

186804

AF XY:

0.000264

show subpopulations

Gnomad AFR exome

AF:

0.000508

Gnomad AMR exome

AF:

0.000168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000687

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000523

Gnomad OTH exome

AF:

0.000397

GnomAD4 exome

AF:

0.000606

AC:

872

AN:

1438860

Hom.:

Cov.:

AF XY:

0.000587

AC XY:

420

AN XY:

715634

show subpopulations

African (AFR)

AF:

0.000482

AC:

AN:

33208

American (AMR)

AF:

0.000204

AC:

AN:

44148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26028

East Asian (EAS)

AF:

0.00

AC:

AN:

39368

South Asian (SAS)

AF:

0.0000352

AC:

AN:

85128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.000739

AC:

820

AN:

1109014

Other (OTH)

AF:

0.000401

AC:

AN:

59878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.000479

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41578

American (AMR)

AF:

0.000261

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000583

Hom.:

Bravo

AF:

0.000450

ESP6500AA

AF:

0.000984

AC:

ESP6500EA

AF:

0.000644

AC:

ExAC

AF:

0.000255

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Polycystic kidney disease, adult type (2)

PKD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.056

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.6

PhyloP100

5.4

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.29

Sift

Uncertain

0.013

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.44

MVP

0.85

ClinPred

0.068

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.61

Mutation Taster

=50/50

(source)

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

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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