Genetic Variant PKD1:p.Gly3583Gly (chr16-2093883-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_001009944.3(PKD1):c.10749C>T(p.Gly3583Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,575,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.208

Publications

0 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 links:

PKD1-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

PKD1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 16-2093883-G-A is Benign according to our data. Variant chr16-2093883-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 586242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.208 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000355 (54/152270) while in subpopulation AFR AF = 0.000866 (36/41552). AF 95% confidence interval is 0.000642. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PKD1	NM_001009944.3	MANE Select	c.10749C>T	p.Gly3583Gly	synonymous	Exon 36 of 46	NP_001009944.3
PKD1	NM_000296.4		c.10746C>T	p.Gly3582Gly	synonymous	Exon 36 of 46	NP_000287.4
PKD1-AS1	NR_135175.1		n.304-838G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PKD1	ENST00000262304.9	TSL:1 MANE Select	c.10749C>T	p.Gly3583Gly	synonymous	Exon 36 of 46	ENSP00000262304.4
PKD1	ENST00000423118.5	TSL:1	c.10746C>T	p.Gly3582Gly	synonymous	Exon 36 of 46	ENSP00000399501.1
PKD1	ENST00000472659.1	TSL:3	n.186C>T		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000349

AC:

AN:

194620

AF XY:

0.000385

show subpopulations

Gnomad AFR exome

AF:

0.000686

Gnomad AMR exome

AF:

0.0000660

Gnomad ASJ exome

AF:

0.00536

Gnomad EAS exome

AF:

0.0000660

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000463

Gnomad OTH exome

AF:

0.000389

GnomAD4 exome

AF:

0.000140

AC:

199

AN:

1423290

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

105

AN XY:

706196

show subpopulations

African (AFR)

AF:

0.000672

AC:

AN:

32716

American (AMR)

AF:

0.0000970

AC:

AN:

41258

Ashkenazi Jewish (ASJ)

AF:

0.00475

AC:

122

AN:

25676

East Asian (EAS)

AF:

0.0000263

AC:

AN:

37982

South Asian (SAS)

AF:

0.0000605

AC:

AN:

82672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0000218

AC:

AN:

1098412

Other (OTH)

AF:

0.000355

AC:

AN:

59164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000355

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41552

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67992

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000752

Hom.:

Bravo

AF:

0.000385

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Benign:1

Jun 21, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Nov 03, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.28

(source)

DANN

Benign

0.61

PhyloP100

-0.21

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over