rs534696523

Variant names:

• chr16-2104493-G-A
• rs534696523
• NM_001009944.3:c.8161+5C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2104493-G-A
• chr16-2104493-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001009944.3(PKD1):​c.8161+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,517,210 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004212
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.02
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-2104493-G-A is Benign according to our data. Variant chr16-2104493-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257013.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000591 (88/148800) while in subpopulation AMR AF = 0.00239 (36/15074). AF 95% confidence interval is 0.00177. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.8161+5C>T		splice_region_variant, intron_variant	Intron 22 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.8161+5C>T		splice_region_variant, intron_variant	Intron 22 of 45	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 88 AN: 148686 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000761

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00239

Gnomad ASJ AF: 0.000871

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000193

Gnomad OTH AF: 0.00243

GnomAD2 exomes AF: 0.000145 AC: 22 AN: 151226 AF XY: 0.000171

Gnomad AFR exome AF: 0.000398

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.000479

Gnomad EAS exome AF: 0.0000837

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.000191 AC: 262 AN: 1368410 Hom.: 1 Cov.: 28 AF XY: 0.000187 AC XY: 127 AN XY: 677670

African (AFR) AF: 0.000989 AC: 30 AN: 30328

American (AMR) AF: 0.000326 AC: 12 AN: 36764

Ashkenazi Jewish (ASJ) AF: 0.000801 AC: 20 AN: 24956

East Asian (EAS) AF: 0.000109 AC: 4 AN: 36836

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4030

European-Non Finnish (NFE) AF: 0.000171 AC: 180 AN: 1055510

Other (OTH) AF: 0.000246 AC: 14 AN: 56912

GnomAD4 genome AF: 0.000591 AC: 88 AN: 148800 Hom.: 0 Cov.: 20 AF XY: 0.000592 AC XY: 43 AN XY: 72622

African (AFR) AF: 0.000759 AC: 30 AN: 39536

American (AMR) AF: 0.00239 AC: 36 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.000871 AC: 3 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 4934

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10504

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

European-Non Finnish (NFE) AF: 0.000193 AC: 13 AN: 67338

Other (OTH) AF: 0.00240 AC: 5 AN: 2080

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000820

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Polycystic kidney disease Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 c.8161+5C>T variant was not identified in the literature nor was it identified in GeneInsight-COGR, LOVD 3.0, ADPKD Mutation Database or PKD1-LOVD. The variant was identified in dbSNP (ID: rs534696523) “With Likely benign allele”, ClinVar (classified likely benign by Prevention Genetics), and in control databases in 34 of 174976 chromosomes at a frequency of 0.0002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 6 of 15076 chromosomes (freq: 0.0004), Latino in 4 of 25344 chromosomes (freq: 0.0002), European Non-Finnish in 17 of 71256 chromosomes (freq: 0.0002), Ashkenazi Jewish in 5 of 8382 chromosomes (freq: 0.0006), East Asian in 1 of 12724 chromosomes (freq: 0.00008), and South Asian in 1 of 23284 chromosomes (freq: 0.00004), while not observed in the Other and European Finnish populations. 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 c.8161+5C>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. Positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing; however, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing for the variant. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Kidney failure Uncertain:1

Jan 14, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.90
DANN	Benign	0.65
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.030
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: rs534696523; hg19: chr16-2154494;