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. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -7 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.
• BP7: Synonymous conserved (PhyloP=-0.589 with no splicing effect.

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

GnomAD2 exomes AF: 0.000237 AC: 36 AN: 151988 AF XY: 0.000207

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 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

African (AFR) AF: 0.0000310 AC: 1 AN: 32214

American (AMR) AF: 0.000537 AC: 21 AN: 39126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25314

East Asian (EAS) AF: 0.000577 AC: 22 AN: 38140

South Asian (SAS) AF: 0.0000862 AC: 7 AN: 81160

European-Finnish (FIN) AF: 0.0000635 AC: 3 AN: 47272

Middle Eastern (MID) AF: 0.000490 AC: 2 AN: 4082

European-Non Finnish (NFE) AF: 0.000217 AC: 235 AN: 1082248

Other (OTH) AF: 0.000292 AC: 17 AN: 58244

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

African (AFR) AF: 0.0000495 AC: 2 AN: 40376

American (AMR) AF: 0.000132 AC: 2 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4970

South Asian (SAS) AF: 0.00 AC: 0 AN: 4710

European-Finnish (FIN) AF: 0.000190 AC: 2 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67604

Other (OTH) AF: 0.00 AC: 0 AN: 2092

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
PhyloP100		-0.59
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs754894798; hg19: chr16-2154524;