NM_001009944.3:c.7913A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001009944.3(PKD1):c.7913A>G(p.His2638Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0555 in 1,477,104 control chromosomes in the GnomAD database, including 8,441 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 4065 hom., cov: 32)

Exomes 𝑓: 0.041 ( 4376 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.35

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010522425).

BP6

Variant 16-2105425-T-C is Benign according to our data. Variant chr16-2105425-T-C is described in ClinVar as [Benign]. Clinvar id is 257008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2105425-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.7913A>G	p.His2638Arg	missense_variant	Exon 21 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.7913A>G	p.His2638Arg	missense_variant	Exon 21 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.181

AC:

27423

AN:

151594

Hom.:

4044

Cov.:

show subpopulations

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.123

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.00348

Gnomad SAS

AF:

0.0275

Gnomad FIN

AF:

0.0759

Gnomad MID

AF:

0.183

Gnomad NFE

AF:

0.0991

Gnomad OTH

AF:

0.179

GnomAD3 exomes

AF:

0.0440

AC:

9388

AN:

213374

Hom.:

1502

AF XY:

0.0383

AC XY:

4521

AN XY:

117948

show subpopulations

Gnomad AFR exome

AF:

0.297

Gnomad AMR exome

AF:

0.0438

Gnomad ASJ exome

AF:

0.0559

Gnomad EAS exome

AF:

0.00240

Gnomad SAS exome

AF:

0.0100

Gnomad FIN exome

AF:

0.0127

Gnomad NFE exome

AF:

0.0343

Gnomad OTH exome

AF:

0.0578

GnomAD4 exome

AF:

0.0411

AC:

54510

AN:

1325394

Hom.:

4376

Cov.:

AF XY:

0.0405

AC XY:

26842

AN XY:

663000

show subpopulations

Gnomad4 AFR exome

AF:

0.264

Gnomad4 AMR exome

AF:

0.0501

Gnomad4 ASJ exome

AF:

0.0937

Gnomad4 EAS exome

AF:

0.00613

Gnomad4 SAS exome

AF:

0.0189

Gnomad4 FIN exome

AF:

0.0551

Gnomad4 NFE exome

AF:

0.0352

Gnomad4 OTH exome

AF:

0.0661

GnomAD4 genome

AF:

0.181

AC:

27486

AN:

151710

Hom.:

4065

Cov.:

AF XY:

0.174

AC XY:

12879

AN XY:

74150

show subpopulations

Gnomad4 AFR

AF:

0.406

Gnomad4 AMR

AF:

0.130

Gnomad4 ASJ

AF:

0.158

Gnomad4 EAS

AF:

0.00349

Gnomad4 SAS

AF:

0.0275

Gnomad4 FIN

AF:

0.0759

Gnomad4 NFE

AF:

0.0992

Gnomad4 OTH

AF:

0.177

Alfa

AF:

0.133

Hom.:

440

Bravo

AF:

0.199

ExAC

AF:

0.0483

AC:

5488

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11571556, 22008521, 22383692) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type

Benign:1

Jul 07, 2020

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: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.His2638Arg variant was identified in 56 of 674 proband chromosomes (frequency: 0.083) from individuals or families with ADPKD or renal disease, and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011, Bouba 2001, McCluskey 2002, Rossetti 2012). All the studies have identified the variant as a polymorphism. The p.His2638Arg variant was identified in the dbSNP (ID: rs9936785) with unknown clinical significance with a minor allele frequency 0.1356 (679 of 5007 chromosomes in 1000 Genome Project). The variant was identified in Exome Aggregation Consortium (ExAC) database (released March 14, 2016) in 4424 of 106234 chromosomes, 501 of which are homozygous (frequency: 0.04164) or 192 of 6148 of European (Finnish), 2099 of 57384 European (Non-Finnish), 177 of 10876 Latino, 1653 of 6824 African, 228 of 16016, South Asians, 33 of 790 Other and in 42 of 8196 East Asians chromosomes. The variant was identified in PKD Mutation Database and classified as â€šÃ„Ãºlikely neutralâ€šÃ„Ã¹; and in GeneInsight the variant was identified by one submitter and classified as benign. In Clinvitae the variant was identified by EmyClass and identified as benign. The p.His2638 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In addition this variant was identified co-occurring with a pathogenic PKD1 variant (PKD1, EXON43, c.11798_11810del, p.Leu3933ArgfsX8) in a patient with a clinical diagnosis of ADPKD. In summary, based on the above information, this variant meets our laboratory criteria to be classified as 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

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.35

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.92

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.16

T;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.72

N;N

REVEL

Benign

0.10

Sift

Benign

0.37

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.0

B;B

Vest4

0.044

ClinPred

0.0044

GERP RS

2.5

Varity_R

0.040

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over