chr16-2118389-G-A

Position:

chr16-2118389-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001009944.3(PKD1):c.603C>T(p.His201=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,244,782 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 16 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 4 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 16-2118389-G-A is Benign according to our data. Variant chr16-2118389-G-A is described in ClinVar as [Benign]. Clinvar id is 433942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2118389-G-A is described in Lovd as [Benign]. Variant chr16-2118389-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.77 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00521 (793/152192) while in subpopulation AFR AF= 0.0183 (762/41530). AF 95% confidence interval is 0.0173. There are 16 homozygotes in gnomad4. There are 365 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 793 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.603C>T	p.His201=	synonymous_variant	5/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9 linkuse as main transcript	c.603C>T	p.His201=	synonymous_variant	5/46	1	NM_001009944.3	P5	P98161-1
PKD1	ENST00000423118.5 linkuse as main transcript	c.603C>T	p.His201=	synonymous_variant	5/46	1		A2	P98161-3

Frequencies

GnomAD3 genomes

AF:

0.00520

AC:

791

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00112

AC:

150

AN:

133840

Hom.:

AF XY:

0.000824

AC XY:

AN XY:

72820

show subpopulations

Gnomad AFR exome

AF:

0.0198

Gnomad AMR exome

AF:

0.000983

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:

0.0000190

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000563

AC:

615

AN:

1092590

Hom.:

Cov.:

AF XY:

0.000480

AC XY:

265

AN XY:

551700

show subpopulations

Gnomad4 AFR exome

AF:

0.0197

Gnomad4 AMR exome

AF:

0.000987

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000271

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000614

Gnomad4 OTH exome

AF:

0.00125

GnomAD4 genome

AF:

0.00521

AC:

793

AN:

152192

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

365

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0183

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.000350

Hom.:

Bravo

AF:

0.00613

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.His201His variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, PKD1-LOVD, PKD1-LOVD 3.0 databases nor in the NHLBI GO Exome Sequencing Project. The variant was identified in dbSNP (ID: rs13334842) as â€šÃ„ÃºNAâ€šÃ„Ã¹ and in the ADPKD Mutation Database as likely neutral. The variant was further identified in the 1000 Genomes Project in 35 of 5000 chromosomes (frequency: 0.007); and in the Exome Aggregation Consortium database (August 8, 2016) in 9 (1 homozygous) of 11240 chromosomes (frequency: 0.0008) in the African population but not seen the East Asian, European (Non-Finnish), Latino, South Asian or 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 p.His201His variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, and 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.36

DANN

Benign

0.53

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