rs375408086

chr16-2104541-G-Achr16-2104541-G-Cchr16-2104541-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001009944.3(PKD1):c.8118C>T(p.Thr2706=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00056 in 1,580,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.33

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-2104541-G-A is Benign according to our data. Variant chr16-2104541-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.34 with no splicing effect.
• BS2: High AC in GnomAd at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8118C>T	p.Thr2706=	synonymous_variant	22/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8118C>T	p.Thr2706=	synonymous_variant	22/46	1	NM_001009944.3	P5

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 56 AN: 149828 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000403

Gnomad SAS AF: 0.000850

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000563

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000463 AC: 71 AN: 153352 Hom.: 0 AF XY: 0.000495 AC XY: 41 AN XY: 82760

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.0000792

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.000334

Gnomad SAS exome AF: 0.000432

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000851

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.000579 AC: 829 AN: 1430936 Hom.: 0 Cov.: 30 AF XY: 0.000569 AC XY: 404 AN XY: 710478

Gnomad4 AFR exome AF: 0.000304

Gnomad4 AMR exome AF: 0.000238

Gnomad4 ASJ exome AF: 0.000117

Gnomad4 EAS exome AF: 0.000540

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.000287

Gnomad4 NFE exome AF: 0.000657

Gnomad4 OTH exome AF: 0.000389

GnomAD4 genome AF: 0.000373 AC: 56 AN: 149946 Hom.: 0 Cov.: 20 AF XY: 0.000342 AC XY: 25 AN XY: 73202

Gnomad4 AFR AF: 0.000248

Gnomad4 AMR AF: 0.0000661

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000404

Gnomad4 SAS AF: 0.000850

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000563

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000442 Hom.: 0

Bravo AF: 0.000393

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PKD1 p.Thr2706Thr variant was not identified in the literature nor was it identified in the Clinvitae, ClinVar, GeneInsight COGR, MutDB, ADPKD Mutation Database, PKD1-LOVD, and PKD1-LOVD 3.0 databases. The variant was identified in the dbSNP database (rs375408086) as “NA” and in the NHLBI GO Exome Sequencing Project in 2 of 8238 European American alleles, the Exome Aggregation Consortium database (March 14, 2016) in 8 of 17150 chromosomes (freq. 0.0005) in the following populations: European (Non-Finnish) in 5 of 6284 chromosomes (freq. 0.0008), South Asian in 2 of 7952 chromosomes (freq.0.0003), African in 1 of 1292 chromosomes (freq. 0.0008), increasing the likelihood this could be a low frequency benign variant. However we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Thr2706Thr 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Polycystic kidney disease, adult type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 19, 2021

- -

PKD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2020

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
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.75
Dann	Benign	0.83

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: rs375408086; hg19: chr16-2154542;