16-2106152-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001009944.3(PKD1):c.7642G>C(p.Glu2548Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,607,232 control chromosomes in the GnomAD database, including 489 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 258 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 231 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.74

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 -16 ACMG points.

BP6

Variant 16-2106152-C-G is Benign according to our data. Variant chr16-2106152-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 257002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2106152-C-G is described in Lovd as [Benign]. Variant chr16-2106152-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.7642G>C	p.Glu2548Gln	missense_variant	Exon 19 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.7642G>C	p.Glu2548Gln	missense_variant	Exon 19 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0298

AC:

4527

AN:

152078

Hom.:

258

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0102

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.0268

GnomAD3 exomes

AF:

0.00674

AC:

1414

AN:

209726

Hom.:

AF XY:

0.00498

AC XY:

576

AN XY:

115646

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.00614

Gnomad ASJ exome

AF:

0.00108

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000702

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000384

Gnomad OTH exome

AF:

0.00227

GnomAD4 exome

AF:

0.00323

AC:

4703

AN:

1455036

Hom.:

231

Cov.:

AF XY:

0.00274

AC XY:

1986

AN XY:

723782

show subpopulations

Gnomad4 AFR exome

AF:

0.107

Gnomad4 AMR exome

AF:

0.00708

Gnomad4 ASJ exome

AF:

0.000883

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000386

Gnomad4 NFE exome

AF:

0.000295

Gnomad4 OTH exome

AF:

0.00766

GnomAD4 genome

AF:

0.0298

AC:

4536

AN:

152196

Hom.:

258

Cov.:

AF XY:

0.0285

AC XY:

2122

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.103

Gnomad4 AMR

AF:

0.0102

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.0265

Alfa

AF:

0.00193

Hom.:

Bravo

AF:

0.0340

ESP6500AA

AF:

0.0750

AC:

303

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.00709

AC:

834

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10577909, 17574468, 22008521, 22383692) -

Polycystic kidney disease, adult type

Benign:1

Jun 02, 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.Glu2548Gln variant was identified in 3 of 604 proband chromosomes (frequency: 0.005) from individuals or families with AKPKD, and was not identified in 200 control chromosomes from healthy individuals (Bataille_2011, Rossetti_2012, Watnick_1999). The variant was also identified in dbSNP (ID: rs rs28369051) with no allele association indicated and listed in 1000 Genomes Project in 192 of 5013 chromosomes (frequency: 0.0383), in NHLBI GO Exome Sequencing Project (ESP) in 2 of 8130 European American (frequency: 0.0002) and 303 in 4042 African American alleles (frequency: 0.075). The variant is also identified in The Exome Aggregation Consortium (ExAC) database (released Mar 14, 2016) in 541 of 500090 chromosomes (frequency: 0.011) of which 30 homozygotes are of African ethnicity increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. Furthermore, the variant is listed in GeneInsight COGR database by LMM 1x as benign, in MutDB 1x as a polymorphism, and in ARPKD database 6x as likely neutral. The p. Glu2548residue 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. Furthermore, the variant amino acid (Gln) is present in dog, increasing the likelihood that this variant does not have clinical significance. 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, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.5

DANN

Benign

0.66

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.49

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.39

N;N

REVEL

Benign

0.060

Sift

Benign

0.57

T;T

Sift4G

Benign

0.58

T;T

Polyphen

0.053

B;B

Vest4

0.14

MVP

0.80

ClinPred

0.00044

GERP RS

-4.0

Varity_R

0.059

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: -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