rs139971481

Positions:

chr16-2108418-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001009944.3(PKD1):c.6749C>T(p.Thr2250Met) variant causes a missense change. The variant allele was found at a frequency of 0.00325 in 1,610,544 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0034 ( 16 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 4.05

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18780598).

BP6

Variant 16-2108418-G-A is Benign according to our data. Variant chr16-2108418-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447996.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr16-2108418-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 330 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.6749C>T	p.Thr2250Met	missense_variant	15/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.6749C>T	p.Thr2250Met	missense_variant	15/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00217

AC:

330

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00464

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00303

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00232

AC:

576

AN:

248540

Hom.:

AF XY:

0.00243

AC XY:

328

AN XY:

135044

show subpopulations

Gnomad AFR exome

AF:

0.000436

Gnomad AMR exome

AF:

0.00267

Gnomad ASJ exome

AF:

0.00170

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.00357

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00337

AC:

4909

AN:

1458208

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

2388

AN XY:

725404

show subpopulations

Gnomad4 AFR exome

AF:

0.000569

Gnomad4 AMR exome

AF:

0.00295

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00157

Gnomad4 FIN exome

AF:

0.000192

Gnomad4 NFE exome

AF:

0.00395

Gnomad4 OTH exome

AF:

0.00286

GnomAD4 genome

AF:

0.00217

AC:

330

AN:

152336

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00303

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00284

Hom.:

Bravo

AF:

0.00274

ESP6500AA

AF:

0.000684

AC:

ESP6500EA

AF:

0.00280

AC:

ExAC

AF:

0.00217

AC:

262

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00387

EpiControl

AF:

0.00492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PKD1: BS1, BS2 -

Polycystic kidney disease, adult type

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 21, 2019	The PKD1 c.6749C>T, p.Thr2250Met variant (rs139971481) has been reported in individuals diagnosed with ADPKD (Irazabal 2011, Perrichot 2000, Reiterova 2013, Rossetti 2012) but has also been found to co-occur with truncating PKD1 variants (Mayo ADPKD database). In one individual, the p.Thr2250Met variant was found in-trans with a truncating PKD1 variant and correlated with a more severe polycystic disorder, suggesting a possible modifier effect (Reiterova 2013). Individuals heterozygous for this variant exhibit either a mild cystic disease or no clinical phenotypes (Kleffman 2012, Reiterova 2013). This variant is found in the non-Finnish European population with an overall allele frequency of 0.35% (444/127104 alleles, including three homozygotes) in the Genome Aggregation Database. The threonine at codon 2250 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Although the population frequency and clinical phenotypes suggest that the p.Thr2250Met may not be a causative variant on its own, its potential effect as a disease modifier cannot be excluded. Thus, the clinical significance of p.Thr2250Met cannot be determined with certainty. References: Mayo ADPKD database: http://pkdb.mayo.edu/ Irazabal M et al. Extended follow-up of unruptured intracranial aneurysms detected by presymptomatic screening in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2011 Jun;6(6):1274-85. Kleffman J et al. Dosage-sensitive network in polycystic kidney and liver disease: multiple mutations cause severe hepatic and neurological complications. J Hepatol. 2012 Aug;57(2):476-7. Perrichot R et al. Novel mutations in the duplicated region of PKD1 gene. Eur J Hum Genet. 2000 May;8(5):353-9. Reiterova J et al. Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele. BMC Nephrol. 2013 Mar 15;14:59. -

PKD1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2024

The PKD1 c.6749C>T variant is predicted to result in the amino acid substitution p.Thr2250Met. This variant has been suggested to be a hypomorphic allele for autosomal dominant polycystic kidney disease (ADPKD) (Reiterová et al. 2013. PubMed ID: 23496908; Irazabal et al. 2011. PubMed ID: 21551026; Perrichot et al. 2000. PubMed ID: 10854095). This type of variant alone in PKD1 probably does not cause ADPKD, but it may act as a hypomorphic allele or modifier to contribute to the disease severity when present in trans with a typical pathogenic or milder PKD1 variant. This variant is reported in 0.35% of alleles (with three homozygotes) in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign due to its relatively high minor allele frequency in the general population, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 24, 2017

- -

Polycystic kidney disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Thr2250Met variant was identified in 9 of 932 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (Irazabal 2011, Paul 2014, Perrichot 2000, Rossetti 2012). The variant was also identified in dbSNP (ID: rs139971481) as â€šÃ„ÃºN/Aâ€šÃ„Ã¹, the ADPKD Mutation Database (classified as likely neutral) and PKD1-LOVD 3.0 (classified as unknown effect). This variant was identified in the 1000 Genomes Project in 7 of 5000 chromosomes (frequency: 0.001), the NHLBI GO Exome Sequencing Project in 24 of 8584 European American and in 3 of 4388 African American alleles, the Exome Aggregation Consortium database (August 8th 2016) in 262 (4 homozygous) of 119152 chromosomes (freq. 0.002) in the following populations: European in 204 of 64980 chromosomes (freq. 0.003), Latino in 26 of 11528 chromosomes (freq. 0.002), Asian in 26 of 16500 chromosomes (freq. 0.002), African in 3 of 10108 chromosomes (freq. 0.0003), Finnish in 2 of 6588 chromosomes (freq. 0.0003) and Other in 1 of 880 chromosomes (freq. 0.001), 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.Thr2250 residue is 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. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In two different case studies suggest the variant has a dosage effect and is most likely an incompletely penetrant allele (Kleffmann 2012, Reiterova 2013). However in the Kleffman study they report a 39 year old female homozygous for the p.The2250Met variant who does not have kidney cysts, suggesting that this variant may not cause typical polycystic kidney disease. This variant located in the REJ domain of PC-1 and cleavage of PC-1 at the GPS site can be affected by variants in this domain, however, analysis by Paul (2014) did not show that p.Thr2250Met variant influences this cleavage. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.19

T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

0.97

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0030

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.90

MVP

0.90

ClinPred

0.012

GERP RS

5.3

Varity_R

0.20

gMVP

0.56

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