chr16-2118389-G-C

Position:

chr16-2118389-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_001009944.3(PKD1):c.603C>G(p.His201Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000413 in 1,244,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. H201?) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 1 hom. )

Consequence

PKD1
NM_001009944.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.77

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 -11 ACMG points.

PM1

In a domain WSC (size 94) in uniprot entity PKD1_HUMAN there are 12 pathogenic changes around while only 5 benign (71%) in NM_001009944.3

BP4

Computational evidence support a benign effect (MetaRNN=0.03233686).

BP6

Variant 16-2118389-G-C is Benign according to our data. Variant chr16-2118389-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 997352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2118389-G-C is described in Lovd as [Likely_benign].

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.603C>G	p.His201Gln	missense_variant	5/46	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.603C>G	p.His201Gln	missense_variant	5/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.603C>G	p.His201Gln	missense_variant	5/46	1		ENSP00000399501.1		P98161-3

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000351

AC:

AN:

133840

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

72820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000696

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000551

Gnomad OTH exome

AF:

0.000245

GnomAD4 exome

AF:

0.000437

AC:

478

AN:

1092596

Hom.:

Cov.:

AF XY:

0.000368

AC XY:

203

AN XY:

551704

show subpopulations

Gnomad4 AFR exome

AF:

0.0000386

Gnomad4 AMR exome

AF:

0.000789

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000298

Gnomad4 NFE exome

AF:

0.000521

Gnomad4 OTH exome

AF:

0.000499

GnomAD4 genome

AF:

0.000237

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000175

Hom.:

Bravo

AF:

0.000348

ExAC

AF:

0.0000886

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 19, 2021

- -

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.His201Gln variant was identified in 1 of 404 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Rossetti 2007). The variant was also identified in dbSNP (ID: rs13334842) as "With Benign allele", and in ADPKD Mutation Database (2x as Likely Neutral). The variant was not identified in ClinVar, LOVD 3.0, or PKD1-LOVD. The variant was identified in control databases in 53 of 159512 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 4 of 4552 chromosomes (freq: 0.0009), Latino in 16 of 24540 chromosomes (freq: 0.0007), European in 33 of 64724 chromosomes (freq: 0.0005), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian 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 p.His201 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In addition, comprehensive mutation screen and evaluation of unclassified variants study by Rossetti (2007) classified the variant as neutral polymorphism with composite variant score less than -5. 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2024

See Variant Classification Assertion Criteria. -

PKD1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2023

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

0.11

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.030

DANN

Benign

0.55

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.46

T;T

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.090

Sift

Benign

0.29

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.034

B;D

Vest4

0.12

MutPred

0.54

Gain of disorder (P = 0.0593);Gain of disorder (P = 0.0593);

MVP

0.76

ClinPred

0.071

GERP RS

-7.1

Varity_R

0.030

gMVP

0.44

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