chr16-2104536-G-A

Position:

chr16-2104536-G-A

Variant summary

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

The NM_001009944.3(PKD1):c.8123C>T(p.Thr2708Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,573,306 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 19 hom., cov: 20)

Exomes 𝑓: 0.016 ( 210 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 9.37

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:

PKD1 (HGNC:):

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=0.011215836).

BP6

Variant 16-2104536-G-A is Benign according to our data. Variant chr16-2104536-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2104536-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-2104536-G-A is described in Lovd as [Benign]. Variant chr16-2104536-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1709/150234) while in subpopulation NFE AF= 0.0188 (1268/67612). AF 95% confidence interval is 0.0179. There are 19 homozygotes in gnomad4. There are 755 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1709 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.8123C>T	p.Thr2708Met	missense_variant	22/46	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.8123C>T	p.Thr2708Met	missense_variant	22/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0114

AC:

1710

AN:

150116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00300

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00434

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00106

Gnomad FIN

AF:

0.0112

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0188

Gnomad OTH

AF:

0.00869

GnomAD3 exomes

AF:

0.00968

AC:

1474

AN:

152302

Hom.:

AF XY:

0.00986

AC XY:

809

AN XY:

82088

show subpopulations

Gnomad AFR exome

AF:

0.00243

Gnomad AMR exome

AF:

0.00704

Gnomad ASJ exome

AF:

0.00453

Gnomad EAS exome

AF:

0.000338

Gnomad SAS exome

AF:

0.00113

Gnomad FIN exome

AF:

0.0109

Gnomad NFE exome

AF:

0.0174

Gnomad OTH exome

AF:

0.00919

GnomAD4 exome

AF:

0.0158

AC:

22553

AN:

1423072

Hom.:

210

Cov.:

AF XY:

0.0155

AC XY:

10936

AN XY:

706240

show subpopulations

Gnomad4 AFR exome

AF:

0.00299

Gnomad4 AMR exome

AF:

0.00655

Gnomad4 ASJ exome

AF:

0.00454

Gnomad4 EAS exome

AF:

0.000207

Gnomad4 SAS exome

AF:

0.00133

Gnomad4 FIN exome

AF:

0.0138

Gnomad4 NFE exome

AF:

0.0188

Gnomad4 OTH exome

AF:

0.0133

GnomAD4 genome

AF:

0.0114

AC:

1709

AN:

150234

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

755

AN XY:

73348

show subpopulations

Gnomad4 AFR

AF:

0.00299

Gnomad4 AMR

AF:

0.0107

Gnomad4 ASJ

AF:

0.00434

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00106

Gnomad4 FIN

AF:

0.0112

Gnomad4 NFE

AF:

0.0188

Gnomad4 OTH

AF:

0.00860

Alfa

AF:

0.0148

Hom.:

Bravo

AF:

0.0104

ESP6500AA

AF:

0.00269

AC:

ESP6500EA

AF:

0.0158

AC:

129

ExAC

AF:

0.00428

AC:

462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2020	This variant is associated with the following publications: (PMID: 27499327, 24374109) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PKD1: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 17, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease, adult type

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 07, 2022	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

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.Thr2708Met variant was identified in 10 of 1016 proband chromosomes (frequency: 0.01) from individuals or families with ADPKD (classified as a polymorphism) and was not identified in 100 control chromosomes from healthy individuals (Bataille 2011, Garcia-Gonzalez 2007, Rossetti 2001, Rossetti 2012). This variant has been seen in one individual from our laboratory as co-occurring with a pathogenic variant increasing the likelihood it may not have clinical significance. The variant was also identified in dbSNP (ID: rs147350387) as â€šÃ„ÃºN/Aâ€šÃ„Ã¹. The variant was identified in the 1000 Genomes Project in 20 of 5000 chromosomes (frequency: 0.004); in NHLBI GO Exome Sequencing Project in 129 of 8168 European American (frequency: 0.016) and 11 of 4082 African American (frequency: 0.0027) alleles. In the Exome Aggregation Consortium database (March 14, 2016) in 114 of 17104 chromosomes of which 1 was homozygous (frequency: 0.00666) in the following populations: 101 of 6264 European (Non-Finnish) â€šÃ„Ã¬ frequency 0.01612; 6 of 7956 South Asian- frequency 0.0007541; 3 of 490 Latinos- frequency 0.006122; 2 of 60 Finnish - frequency 0.03333; 1 of 1246 African - frequency 0.0008026 and 1 of 164 Other- frequency: 0.006098) alleles. The variant was identified in ADPKD Mutation Database classified as likely neutral. The p.Thr2708 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. 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

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

Oct 09, 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

0.29

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.59

MVP

0.78

ClinPred

0.016

GERP RS

4.2

Varity_R

0.40

gMVP

0.71

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