rs116236042

Positions:

• chr16-2090926-G-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.11961C>T​(p.Ala3987Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,582,776 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (83 hom., cov: 34)
  • Exomes 𝑓: 0.0019 (89 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.569

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-2090926-G-A is Benign according to our data. Variant chr16-2090926-G-A is described in ClinVar as [Benign]. Clinvar id is 256911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2090926-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.569 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.11961C>T	p.Ala3987Ala	synonymous_variant	43/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.11961C>T	p.Ala3987Ala	synonymous_variant	43/46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2683 AN: 152192 Hom.: 82 Cov.: 34

Gnomad AFR AF: 0.0606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00460 AC: 870 AN: 189300 Hom.: 21 AF XY: 0.00342 AC XY: 362 AN XY: 105740

Gnomad AFR exome AF: 0.0686

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000360

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.00188 AC: 2688 AN: 1430466 Hom.: 89 Cov.: 34 AF XY: 0.00159 AC XY: 1131 AN XY: 710778

Gnomad4 AFR exome AF: 0.0668

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.000895

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000711

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000535

Gnomad4 OTH exome AF: 0.00393

GnomAD4 genome AF: 0.0177 AC: 2694 AN: 152310 Hom.: 83 Cov.: 34 AF XY: 0.0170 AC XY: 1268 AN XY: 74470

Gnomad4 AFR AF: 0.0607

Gnomad4 AMR AF: 0.00751

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00780 Hom.: 6

Bravo AF: 0.0211

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 11, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Ala3987Ala variant was identified in 2 of 90 proband chromosomes (frequency: 0.22) from individuals or families with ADPKD (Rossetti 2002). This variant was identified in the 1000 Genomes Project in 113 of 5000 chromosomes (frequency: 0.0226), NHLBI GO Exome Sequencing Project in 3 of 8366 European American alleles (frequency: 0.000358594), and 195 of 4250 African American alleles (frequency: 0.045882353), Exome Aggregation Consortium database (August 8, 2016) in 378 (7 homozygous) of 47294 chromosomes (frequency: 0.007993) in the following populations: African in 353 of 3340 chromosomes (frequency: 0.1057) Latino in 19 of 3822 chromosomes (frequency: 0.004971) European (Non-Finnish) in 4 of 23962 chromosomes (frequency: 0.0001669) South Asian in 1 of 10920 chromosomes (frequency: 0.00009158) and Other in 1 of 344 chromosomes (frequency: 00.002907), but was not seen in East Asian and European (Finnish) populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. 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 also identified in dbSNP (ID: rs116236042) as “With Benign allele”, ClinVar and Clinvitae (benign, by Prevention Genetics), ADPKD Mutation Database (Likely neutral). The p.Ala3987Ala 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, 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	-0.86
CADD	Benign	6.7
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs116236042; hg19: chr16-2140927;