NM_001009944.3:c.8247G>A

Variant names:

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.8247G>A(p.Ala2749Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,608,824 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.46

Publications

1 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 16-2103810-C-T is Benign according to our data. Variant chr16-2103810-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 440127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.46 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00101 (152/150810) while in subpopulation AMR AF = 0.0023 (35/15198). AF 95% confidence interval is 0.0017. There are 0 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8247G>A	p.Ala2749Ala	synonymous_variant	Exon 23 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.8247G>A	p.Ala2749Ala	synonymous_variant	Exon 23 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

152

AN:

150692

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000710

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00231

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000953

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00127

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.000790

AC:

195

AN:

246752

AF XY:

0.000765

show subpopulations

Gnomad AFR exome

AF:

0.000325

Gnomad AMR exome

AF:

0.00189

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00110

AC:

1610

AN:

1458014

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

729

AN XY:

725308

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33392

American (AMR)

AF:

0.00177

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000697

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.0000576

AC:

AN:

52052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4138

European-Non Finnish (NFE)

AF:

0.00129

AC:

1432

AN:

1111602

Other (OTH)

AF:

0.00123

AC:

AN:

60168

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

190

286

381

476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.00101

AC:

152

AN:

150810

Hom.:

Cov.:

AF XY:

0.000870

AC XY:

AN XY:

73574

show subpopulations

African (AFR)

AF:

0.000707

AC:

AN:

40994

American (AMR)

AF:

0.00230

AC:

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

4968

South Asian (SAS)

AF:

0.00

AC:

AN:

4724

European-Finnish (FIN)

AF:

0.0000953

AC:

AN:

10488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00127

AC:

AN:

67680

Other (OTH)

AF:

0.000477

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.000672

Hom.:

Bravo

AF:

0.00107

EpiCase

AF:

0.00125

EpiControl

AF:

0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 20, 2016

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKD1: BP4, BP7 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKD1 p.Ala2749= variant was identified in 2 of 1044 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Carrera 2016, Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs143265128) as â€šÃ„ÃºNAâ€šÃ„Ã¹, the ADPKD Mutation Database (likely neurtal), in the 1000 Genomes Project (freq. 0.0008), the ESP Project in the European population (freq. 0.002), in the genome aggregation consortium (freq 0.0008) an in the Exome Aggregation Consortium database (August 8th 2016) in 80 of 112864 chromosomes (freq. 0.0007) in the following populations: Latino in 18 of 11034 chromosomes (freq. 0.002), Other in 1 of 828 chromosomes (freq. 0.001), European (Non-Finnish) in 53 of 61588 chromosomes (freq. 0.0009), African in 6 of 8872 chromosomes (freq. 0.0007), and South Asian in 2 of 16114 chromosomes (freq. 0.0001), but was not seen in East Asian or Finish populations, increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala2749= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified by our laboratory in a patient with ADPKD with a co-occurring pathogenic PKD1 variant (p.Gln739X), increasing the likelihood that the p.Ala2749= variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

2.8

(source)

DANN

Benign

0.91

PhyloP100

-1.5

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over