rs754894798

Variant names:

• chr16-2104523-G-A
• rs754894798
• NM_001009944.3:c.8136C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2104523-G-A
• chr16-2104523-G-C
• chr16-2104523-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BP6_Moderate BP7 BS2_Supporting

The NM_001009944.3(PKD1):​c.8136C>T​(p.Ile2712Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,557,892 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 0.00011 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.589

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-2104523-G-A is Benign according to our data. Variant chr16-2104523-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 448013.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2104523-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.589 with no splicing effect.
• BS2: High AC in GnomAd4 at 17 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.8136C>T	p.Ile2712Ile	synonymous_variant	Exon 22 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.8136C>T	p.Ile2712Ile	synonymous_variant	Exon 22 of 46	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 17 AN: 149974 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000497

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000237 AC: 36 AN: 151988 Hom.: 0 AF XY: 0.000207 AC XY: 17 AN XY: 81962

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000677

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000424

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000462

GnomAD4 exome AF: 0.000219 AC: 308 AN: 1407800 Hom.: 0 Cov.: 30 AF XY: 0.000206 AC XY: 144 AN XY: 697830

Gnomad4 AFR exome AF: 0.0000310

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000577

Gnomad4 SAS exome AF: 0.0000862

Gnomad4 FIN exome AF: 0.0000635

Gnomad4 NFE exome AF: 0.000217

Gnomad4 OTH exome AF: 0.000292

GnomAD4 genome AF: 0.000113 AC: 17 AN: 150092 Hom.: 0 Cov.: 20 AF XY: 0.000109 AC XY: 8 AN XY: 73286

Gnomad4 AFR AF: 0.0000495

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000201

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000234 Hom.: 0

Bravo AF: 0.000196

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 30, 2016

Athena Diagnostics

Significance: Likely 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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 p.Ile2712= variant was not identified in the literature, nor was it identified in GeneInsight COGR, ClinVar, Clinvitae, MutDB, PKD1-LOVD, or PKD1-LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs754894798) as “N/A”, ADPKD Mutation Database (classified as likely neutral), the genome Aggregation Database (beta, October 19th 2016) in 37 of 176006 chromosomes (freq. 0.0002), the Exome Aggregation Consortium database (August 8th 2016) in 4 of 17182 chromosomes (freq. 0.0002) in the following populations: European in 3 of 6330 chromosomes (freq. 0.0005), Latino in 1 of 516 chromosomes (freq. 0.002), but was not seen in African, Asian, Finnish and Other populations. The p.Ile2712= 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, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.80
DANN	Benign	0.80

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: rs754894798; hg19: chr16-2154524;