16-2109713-C-T

Variant names:

• chr16-2109713-C-T
• rs143916489
• NM_001009944.3:c.5454G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):​c.5454G>A​(p.Ala1818Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00759 in 1,602,118 control chromosomes in the GnomAD database, including 776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (421 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (355 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -5.37

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 16-2109713-C-T is Benign according to our data. Variant chr16-2109713-C-T is described in ClinVar as [Benign]. Clinvar id is 256978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2109713-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.5454G>A	p.Ala1818Ala	synonymous_variant	Exon 15 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.5454G>A	p.Ala1818Ala	synonymous_variant	Exon 15 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5934 AN: 152180 Hom.: 418 Cov.: 33

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.0336

GnomAD3 exomes AF: 0.00987 AC: 2216 AN: 224612 Hom.: 122 AF XY: 0.00731 AC XY: 900 AN XY: 123050

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.00807

Gnomad ASJ exome AF: 0.00630

Gnomad EAS exome AF: 0.000238

Gnomad SAS exome AF: 0.0000691

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000628

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00428 AC: 6202 AN: 1449820 Hom.: 355 Cov.: 34 AF XY: 0.00369 AC XY: 2657 AN XY: 720454

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.00915

Gnomad4 ASJ exome AF: 0.00803

Gnomad4 EAS exome AF: 0.000204

Gnomad4 SAS exome AF: 0.000153

Gnomad4 FIN exome AF: 0.0000390

Gnomad4 NFE exome AF: 0.000366

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.0391 AC: 5952 AN: 152298 Hom.: 421 Cov.: 33 AF XY: 0.0378 AC XY: 2817 AN XY: 74464

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0172

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.0332

Alfa AF: 0.00348 Hom.: 5

Bravo AF: 0.0446

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: 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

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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: 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.Ala1818Ala was identified in 1 of 460 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD, and was not identified in 68 control chromosomes from healthy individuals (Rossetti 2012). The variant is listed in the dbSNP database (ID#: rs143916489) The variant was also identified in the 1000 Genomes Project in 236 of 5011 chromosomes (frequency: 0.0471) and in the NHLBI GO Exome Sequencing Project in 9 of 8516 European American (frequency: 0.001) and 554 of 4312 African American (frequency: 0.128) alleles. Furthermore, the variant is listed in the Exome Aggregation Consortium database (March 14, 2016) in 1081 of 49564 chromosomes (frequency: 0.021) including in the African population 969 (61 homozygous) of 4458 chromosomes (freq. 0.2174), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. We cannot be certain that variant data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant is also identified in GeneInsight COGR and listed in the ADPKD Mutation Database 5x as likely neutral. The p.Ala1818Ala 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, 4 of 5 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
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.28
DANN	Benign	0.62

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

Other links and lift over

dbSNP: rs143916489; hg19: chr16-2159714;