Genetic Variant PKD1:p.Ala898Ala (chr16-2114329-T-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001009944.3(PKD1):c.2694A>C(p.Ala898Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,610,450 control chromosomes in the GnomAD database, including 380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 25 hom., cov: 32)

Exomes 𝑓: 0.020 ( 355 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.13

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

new If you want to explore the variant's impact on the transcript NM_001009944.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 16-2114329-T-G is Benign according to our data. Variant chr16-2114329-T-G is described in ClinVar as Benign. ClinVar VariationId is 256935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.13 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0132 (2017/152316) while in subpopulation NFE AF = 0.022 (1493/68018). AF 95% confidence interval is 0.021. There are 25 homozygotes in GnomAd4. There are 935 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AD,AR gene

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.2694A>C	p.Ala898Ala	synonymous	Exon 11 of 46	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.2694A>C	p.Ala898Ala	synonymous	Exon 11 of 46	NP_000287.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PKD1	ENST00000262304.9	TSL:1 MANE Select	c.2694A>C	p.Ala898Ala	synonymous	Exon 11 of 46	ENSP00000262304.4	P98161-1
PKD1	ENST00000423118.5	TSL:1	c.2694A>C	p.Ala898Ala	synonymous	Exon 11 of 46	ENSP00000399501.1	P98161-3
PKD1	ENST00000488185.2	TSL:5	c.470+3160A>C		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2017

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00870

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0219

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0130

AC:

3211

AN:

247924

AF XY:

0.0129

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.00681

Gnomad ASJ exome

AF:

0.00322

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0164

Gnomad NFE exome

AF:

0.0213

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0205

AC:

29858

AN:

1458134

Hom.:

355

Cov.:

AF XY:

0.0201

AC XY:

14581

AN XY:

725394

show subpopulations

African (AFR)

AF:

0.00341

AC:

114

AN:

33392

American (AMR)

AF:

0.00689

AC:

308

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00299

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.00277

AC:

239

AN:

86156

European-Finnish (FIN)

AF:

0.0171

AC:

892

AN:

52146

Middle Eastern (MID)

AF:

0.00314

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0243

AC:

27024

AN:

1111640

Other (OTH)

AF:

0.0197

AC:

1187

AN:

60168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1734

3468

5202

6936

8670

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1030

2060

3090

4120

5150

<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:

0.0132

AC:

2017

AN:

152316

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

935

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00366

AC:

152

AN:

41574

American (AMR)

AF:

0.00869

AC:

133

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00373

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0165

AC:

175

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0220

AC:

1493

AN:

68018

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

112

224

336

448

560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0126

Hom.:

Bravo

AF:

0.0122

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0211

EpiControl

AF:

0.0171

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

Polycystic kidney disease, adult type (2)

Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.27

(source)

DANN

Benign

0.47

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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