rs201238819

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS1

The NM_001009944.3(PKD1):c.8087T>G(p.Leu2696Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2696F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00041 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.659

Publications

12 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077767074).

BP6

Variant 16-2104572-A-C is Benign according to our data. Variant chr16-2104572-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 433983.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0015 (219/145524) while in subpopulation AMR AF = 0.00388 (57/14680). AF 95% confidence interval is 0.00308. There are 0 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.8087T>G	p.Leu2696Arg	missense_variant	Exon 22 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.8087T>G	p.Leu2696Arg	missense_variant	Exon 22 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

218

AN:

145412

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00187

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00389

Gnomad ASJ

AF:

0.00178

Gnomad EAS

AF:

0.000846

Gnomad SAS

AF:

0.00133

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.00300

GnomAD2 exomes

AF:

0.00108

AC:

184

AN:

170576

AF XY:

0.00112

show subpopulations

Gnomad AFR exome

AF:

0.00167

Gnomad AMR exome

AF:

0.00203

Gnomad ASJ exome

AF:

0.00245

Gnomad EAS exome

AF:

0.000145

Gnomad FIN exome

AF:

0.000160

Gnomad NFE exome

AF:

0.000886

Gnomad OTH exome

AF:

0.00194

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000412

AC:

596

AN:

1447962

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

300

AN XY:

720112

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00145

AC:

AN:

33218

American (AMR)

AF:

0.00174

AC:

AN:

44198

Ashkenazi Jewish (ASJ)

AF:

0.000734

AC:

AN:

25892

East Asian (EAS)

AF:

0.00134

AC:

AN:

39480

South Asian (SAS)

AF:

0.000341

AC:

AN:

85014

European-Finnish (FIN)

AF:

0.0000793

AC:

AN:

50416

Middle Eastern (MID)

AF:

0.000729

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.000301

AC:

333

AN:

1105806

Other (OTH)

AF:

0.000501

AC:

AN:

59822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.349

Heterozygous variant carriers

102

127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00150

AC:

219

AN:

145524

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

107

AN XY:

70886

show subpopulations

African (AFR)

AF:

0.00189

AC:

AN:

39180

American (AMR)

AF:

0.00388

AC:

AN:

14680

Ashkenazi Jewish (ASJ)

AF:

0.00178

AC:

AN:

3362

East Asian (EAS)

AF:

0.000848

AC:

AN:

4718

South Asian (SAS)

AF:

0.00133

AC:

AN:

4524

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

65720

Other (OTH)

AF:

0.00297

AC:

AN:

2018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.000692

Hom.:

ExAC

AF:

0.000474

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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.Leu2696Arg variant was identified in 14 of 286 proband chromosomes (frequency: 0.049) from individuals or families with ADPKD, and was not identified in 100 control chromosomes from healthy individuals (Phakdeekitcharoen 2001, Bataille 2011, Yu 2011). The p.Leu2696Arg variant was identified in the dbSNP (ID: rs201238819) with no known clinical significance. The variant was not identified in NHLBI Exome Sequencing Project (Exome Variant Server). The variant was identified in Exome Aggregation Consortium (March 14, 2016), in 42 of 19230 chromosomes (frequency: 0.002) or 10 of 8070 South Asians, 24 of 7400 European (Non-Finnish), 2 of 628 Latino, 5 of 1616 African and 1 of 178 Other populations and not found in East Asian and European (Finnish), increasing the likelihood this could be a low frequency benign variant. The variant was identified in the PKD Mutation Database and was classified as likely neutral. The p.Leu2696 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In a study of 41 Thai probands with ADPKD and pathogenic variants in the replicated portion of the PKD1 gene, the p.Leu2696Arg variant was identified to occur in non-conservative region within the REJ domain, but its effect on the three-dimensional structure is unknown. Glutamic acid and arginine are observed in the corresponding positions of Fugu and murine polycystin-1, respectively, suggesting a noncritical role for a nonpolar residue at this location (Phakdeekitcharoen 2001). In ADPKD family studies, the variant was identified in a fetus with cystic kidneys resembling ADPKD on ultrasound however it co-occurred with a de novo PKD1 â€šÃ„Ãºlikely pathogenicâ€šÃ„Ã¹ variant (c.9222C>G, p.Asn3074Lys. The fetus was also identified to carry a HNF1Å’â‰¤ â€šÃ„Ãºhighly likely pathogenicâ€šÃ„Ã¹ variant (c.883C>T, p.Arg295Cys) which was also identified in the father and paternal grandmother who had cystic kidneys consistent with the HNF1Å’â‰¤ phenotype. The PKD1 p.Leu2696Arg variant was inherited from the mother with a normal renal phenotype. (Bergmann_2011_22034641). 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 Benign. -

not provided

Benign:1

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PKD1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

4.7

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.044

T;T

M_CAP

Benign

0.051

MetaRNN

Benign

0.0078

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-2.2

N;N

PhyloP100

0.66

PrimateAI

Benign

0.43

PROVEAN

Benign

2.1

N;N

REVEL

Benign

0.25

Sift

Benign

0.89

T;T

Sift4G

Benign

0.93

T;T

Polyphen

0.0

B;B

Vest4

0.16

MVP

0.76

ClinPred

0.00030

GERP RS

-1.7

Varity_R

0.055

gMVP

0.16

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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