rs551353498

Positions:

chr16-2119356-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_001009944.3(PKD1):c.238C>T(p.Arg80Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 1,464,496 control chromosomes in the GnomAD database, including 14 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 14 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.41

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:

ENSG00000260447 (HGNC:):

ENSG00000260447 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040474236).

BP6

Variant 16-2119356-G-A is Benign according to our data. Variant chr16-2119356-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 586259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000528 (693/1312186) while in subpopulation SAS AF= 0.0078 (606/77706). AF 95% confidence interval is 0.00728. There are 14 homozygotes in gnomad4_exome. There are 509 alleles in male gnomad4_exome subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High AC in GnomAd4 at 36 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.238C>T	p.Arg80Trp	missense_variant	2/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.238C>T	p.Arg80Trp	missense_variant	2/46	1	NM_001009944.3	ENSP00000262304.4	P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.238C>T	p.Arg80Trp	missense_variant	2/46	1		ENSP00000399501.1	P98161-3
ENSG00000260447	ENST00000562027.1 linkuse as main transcript	n.150G>A		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00158

AC:

216

AN:

136402

Hom.:

AF XY:

0.00219

AC XY:

162

AN XY:

74078

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000189

Gnomad SAS exome

AF:

0.00934

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.000483

GnomAD4 exome

AF:

0.000528

AC:

693

AN:

1312186

Hom.:

Cov.:

AF XY:

0.000781

AC XY:

509

AN XY:

651462

show subpopulations

Gnomad4 AFR exome

AF:

0.0000995

Gnomad4 AMR exome

AF:

0.0000281

Gnomad4 ASJ exome

AF:

0.0000404

Gnomad4 EAS exome

AF:

0.0000565

Gnomad4 SAS exome

AF:

0.00780

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000394

Gnomad4 OTH exome

AF:

0.000651

GnomAD4 genome

AF:

0.000236

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00560

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000854

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.00271

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	See Variant Classification Assertion Criteria. -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Arg80Trp variant was not identified in the literature nor was it identified in the ClinVar, COGR, LOVD 3.0, or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs551353498), ADPKD Mutation Database (classified indeterminate), and in control databases in 227 of 162048 chromosomes (7 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: â€šÃ„ÃºOtherâ€šÃ„Ã¹ in 1 of 4576 chromosomes (freq: 0.0002), Latino in 1 of 24584 chromosomes (freq: 0.00004), European Non-Finnish in 3 of 66780 chromosomes (freq: 0.00005), East Asian in 2 of 11550 chromosomes (freq: 0.0002), and South Asian in 220 (7 homozygous) of 22550 chromosomes (freq: 0.01), it was not observed in the African, Ashkenazi Jewish and European Finnish populations. 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 variant was identified by our laboratory in 1 individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.1391delT, p.Leu464GlnfsX94), increasing the likelihood that the p.Arg80Trp variant does not have clinical significance. The p.Arg80 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Trp to the protein; this information is not very predictive of 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 this variant meets our laboratory criteria to be classified as benign. -

PKD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2019

This variant is classified as likely 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

0.087

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

0.010

Eigen_PC

Benign

-0.082

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.6

L;L

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.015

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

0.90

P;D

Vest4

0.19

MutPred

0.51

Gain of catalytic residue at L78 (P = 0.0698);Gain of catalytic residue at L78 (P = 0.0698);

MVP

0.64

ClinPred

0.060

GERP RS

3.2

Varity_R

0.088

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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