rs139744826

Positions:

chr16-2111678-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.3489C>T(p.Phe1163Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,577,442 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 32 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 21 hom. )

Consequence

PKD1
NM_001009944.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.143

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 16-2111678-G-A is Benign according to our data. Variant chr16-2111678-G-A is described in ClinVar as [Benign]. Clinvar id is 256952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2111678-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.143 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1774/152250) while in subpopulation AFR AF= 0.0387 (1607/41548). AF 95% confidence interval is 0.0371. There are 32 homozygotes in gnomad4. There are 874 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1774 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3 linkuse as main transcript	c.3489C>T	p.Phe1163Phe	synonymous_variant	15/46	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.3489C>T	p.Phe1163Phe	synonymous_variant	15/46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1764

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00700

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00913

GnomAD3 exomes

AF:

0.00313

AC:

584

AN:

186678

Hom.:

AF XY:

0.00248

AC XY:

250

AN XY:

100830

show subpopulations

Gnomad AFR exome

AF:

0.0383

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.00578

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000117

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.00426

GnomAD4 exome

AF:

0.00141

AC:

2003

AN:

1425192

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

893

AN XY:

705932

show subpopulations

Gnomad4 AFR exome

AF:

0.0384

Gnomad4 AMR exome

AF:

0.00250

Gnomad4 ASJ exome

AF:

0.00723

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000134

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000222

Gnomad4 OTH exome

AF:

0.00330

GnomAD4 genome

AF:

0.0117

AC:

1774

AN:

152250

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

874

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0387

Gnomad4 AMR

AF:

0.00699

Gnomad4 ASJ

AF:

0.00750

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00903

Alfa

AF:

0.00402

Hom.:

Bravo

AF:

0.0132

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2020	- -

Polycystic kidney disease, adult type

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 04, 2018

- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD1 p.Phe1163Phe variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from individuals or families with ADPKD (Garcia-Gonzalez 2007), ClinVar and Clinvitae (as Benign by Prevention Genetics), ADPKD Mutation Database (Likely neutral), GeneInsight-COGR (as Benign by a clinical laboratory). The variant was identified in dbSNP (ID: rs139744826) as â€šÃ„ÃºWith Benign alleleâ€šÃ„Ã¹, with a minor allele frequency of 0.01 (58 of 5000 chromosomes in 1000 Genomes Project), the NHLBI GO Exome Sequencing Project in 4 of 8468 European American (frequency: 0.0005) and in 161 of 4280 African American alleles (frequency: 0.04), the Exome Aggregation Consortium database (August 8, 2016) in 228 (3 homozygous) of 30390 chromosomes (frequency: 0.008) in the following populations: African in 191 of 3092 chromosomes (frequency:0.06), Latino in 12 of 1416 chromosomes (frequency: 0.008), European (Non-Finnish) in 22 of 14238 chromosomes (frequency: 0.002), South Asian in 1 of 9058 chromosomes (frequency: 0.0001), and in Other in 2 of 264 chromosomes (frequency: 0.008)and was not identified in East Asian and Finnish populations, increasing the likelihood this could be a low frequency benign variant. 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.12178C>T, p.Gln4060X), increasing the likelihood that the variant does not have clinical significance. The p.Phe1163Phe 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.043

DANN

Benign

0.86

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