NM_001009944.3:c.11976C>G

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.11976C>G(p.Ala3992Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,592,700 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 4 hom., cov: 34)

Exomes 𝑓: 0.0055 ( 38 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.169

Publications

3 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=-0.73).

BP6

Variant 16-2090911-G-C is Benign according to our data. Variant chr16-2090911-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.169 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00322 (491/152372) while in subpopulation NFE AF = 0.00562 (382/68024). AF 95% confidence interval is 0.00515. There are 4 homozygotes in GnomAd4. There are 206 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.11976C>G	p.Ala3992Ala	synonymous_variant	Exon 43 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.11976C>G	p.Ala3992Ala	synonymous_variant	Exon 43 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00322

AC:

491

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00562

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00302

AC:

617

AN:

204404

AF XY:

0.00288

show subpopulations

Gnomad AFR exome

AF:

0.00100

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.000436

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00119

Gnomad NFE exome

AF:

0.00507

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00550

AC:

7915

AN:

1440328

Hom.:

Cov.:

AF XY:

0.00533

AC XY:

3818

AN XY:

716472

show subpopulations

African (AFR)

AF:

0.000781

AC:

AN:

33288

American (AMR)

AF:

0.00180

AC:

AN:

43258

Ashkenazi Jewish (ASJ)

AF:

0.000580

AC:

AN:

25858

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39350

South Asian (SAS)

AF:

0.00162

AC:

138

AN:

85214

European-Finnish (FIN)

AF:

0.00133

AC:

AN:

39882

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00663

AC:

7344

AN:

1107860

Other (OTH)

AF:

0.00424

AC:

254

AN:

59872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

501

1001

1502

2002

2503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

282

564

846

1128

1410

<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:

0.00322

AC:

491

AN:

152372

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

206

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41598

American (AMR)

AF:

0.00189

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00186

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00562

AC:

382

AN:

68024

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000794

Hom.:

Bravo

AF:

0.00324

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

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

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKD1: BP4, BP7, BS2 -

Jan 07, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11967008, 10987650, 10200984) -

Apr 06, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease, adult type

Benign:1

May 24, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKD1 p.Ala3992Ala variant was identified in 4 of 732 proband chromosomes (frequency: 0.005) from individuals or families with ADPKD (Badenas 1999, Perrichot 1999, Rossetti 2002). The variant was also identified in dbSNP (ID: rs112387277) as â€šÃ„ÃºWith Likely benign alleleâ€šÃ„Ã¹, Clinvitae (classified as likely benign), ClinVar (classified as likely benign by Prevention Genetics), ADPKD Mutation Database (classified as likely neutral), the 1000 Genomes Project in 4 of 5000 chromosomes (frequency: 0.0008), the NHLBI GO Exome Sequencing Project in 29 of 8486 European American and in 1 of 4288 African American alleles, the Exome Aggregation Consortium database (August 8th 2016) in 262 (1 homozygous) of 59468 chromosomes (freq. 0.004) in the following populations: European in 196 of 31204 chromosomes (freq. 0.006), Asian in 30 of 11894 chromosomes (freq. 0.003), Latino in 21 of 5190 chromosomes (freq. 0.004), Finnish in 8 of 2492 chromosomes (freq. 0.003), African in 7 of 4082 chromosomes (freq. 0.002), increasing the likelihood this could be a low frequency benign variant. The p.Ala3992Ala 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. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Jan 01, 2019

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.5

(source)

DANN

Benign

0.54

PhyloP100

0.17

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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