rs140980374

Positions:

chr16-2110903-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001009944.3(PKD1):c.4264G>A(p.Ala1422Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00544 in 1,611,388 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0055 ( 48 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0600

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=0.004206896).

BP6

Variant 16-2110903-C-T is Benign according to our data. Variant chr16-2110903-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2110903-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00549 (8012/1459086) while in subpopulation MID AF= 0.0489 (233/4762). AF 95% confidence interval is 0.0438. There are 48 homozygotes in gnomad4_exome. There are 3989 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.

BS2

High AC in GnomAd4 at 758 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.4264G>A	p.Ala1422Thr	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.4264G>A	p.Ala1422Thr	missense_variant	15/46	1	NM_001009944.3	ENSP00000262304	P5	P98161-1

Frequencies

GnomAD3 genomes

AF:

0.00499

AC:

759

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.0343

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.00613

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00591

AC:

1472

AN:

248902

Hom.:

AF XY:

0.00603

AC XY:

816

AN XY:

135334

show subpopulations

Gnomad AFR exome

AF:

0.000627

Gnomad AMR exome

AF:

0.00385

Gnomad ASJ exome

AF:

0.0337

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00477

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00673

Gnomad OTH exome

AF:

0.0102

GnomAD4 exome

AF:

0.00549

AC:

8012

AN:

1459086

Hom.:

Cov.:

AF XY:

0.00550

AC XY:

3989

AN XY:

725832

show subpopulations

Gnomad4 AFR exome

AF:

0.00179

Gnomad4 AMR exome

AF:

0.00391

Gnomad4 ASJ exome

AF:

0.0313

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00428

Gnomad4 FIN exome

AF:

0.00150

Gnomad4 NFE exome

AF:

0.00521

Gnomad4 OTH exome

AF:

0.00802

GnomAD4 genome

AF:

0.00498

AC:

758

AN:

152302

Hom.:

Cov.:

AF XY:

0.00485

AC XY:

361

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00660

Gnomad4 ASJ

AF:

0.0343

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00613

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00753

Hom.:

Bravo

AF:

0.00506

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.00838

AC:

ExAC

AF:

0.00593

AC:

717

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00872

EpiControl

AF:

0.00836

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PKD1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	This variant is associated with the following publications: (PMID: 17582161, 22383692) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 20, 2019

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

PKD1, EXON15, c.4264G>A, p.Ala1422Thr, (Alias c.4475G>A), Heterozygous, Benign The PKD1 p.Ala1422Thr variant was identified in 3 of 864 proband chromosomes (frequency: 0.003) from individuals or families with ADPKD, and was not identified in 242 control chromosomes from healthy individuals (Rossetti 2007, Rossetti 2012). The variant was also identified in dbSNP (ID: rs140980374) â€šÃ„ÃºWith clinical significance allele not availableâ€šÃ„Ã¹, in 1000 Genomes Project in 22 of 5000 chromosomes (frequency: 0.004), in NHLBI GO Exome Sequencing Project (ESP) in 72 of 8592 European American (frequency: 0.008) and 9 in 4394 (frequency: 0.002) African American alleles. This variant was identified in the Exome Aggregation Consortium database (March 2016) in 713 (5 homozygous) of 118566 chromosomes (freq. 0.006) in the following populations: other in 10 of 880 chromosomes (freq. 0.01), European (Non-Finnish) in 565 of 64594 chromosomes (freq. 0.009), South Asian in 76 of 16504 chromosomes (freq. 0.005), Latino in 45 of 11538 chromosomes (freq. 0.004), Finnish in 7 of 6602 chromosomes (freq. 0.001), and African in 10 of 9854 chromosomes (freq. 0.001), but was not seen in the East Asian populations, increasing the likelihood this could be a low frequency benign variant. However we cannot be certain that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. Furthermore, the variant is listed in the GeneInsight COGR database as benign, as likely neutral in the ADPKD Mutation Database, and listed with no classification in the PKD1-LOVD 3.0 database. The p.Ala1422 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. Furthermore, the variant amino acid â€šÃ„ÃºThreonineâ€šÃ„Ã¹ is present in macaque, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was observed as co-occurring with another pathogenic variant in one individual identified by our laboratory, increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Likely benign, criteria provided, single submitter

research

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

Jan 01, 2019

- -

PKD1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.13

DANN

Benign

0.58

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.24

T;T

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.090

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.14

N;N

REVEL

Benign

0.018

Sift

Benign

0.41

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.083

B;B

Vest4

0.085

MVP

0.55

ClinPred

0.00098

GERP RS

-1.8

Varity_R

0.027

gMVP

0.16

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