rs534696523

chr16-2104493-G-Achr16-2104493-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001009944.3(PKD1):c.8161+5C>T variant causes a splice donor 5th base, 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: PKD1 NM_001009944.3 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.0004212
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: -1.02

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 -16 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 [Likely_benign]. Clinvar id is 257013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2104493-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 88 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.8161+5C>T		splice_donor_5th_base_variant, intron_variant		ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.8161+5C>T		splice_donor_5th_base_variant, intron_variant		1	NM_001009944.3	P5

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

GnomAD3 exomes AF: 0.000145 AC: 22 AN: 151226 Hom.: 0 AF XY: 0.000171 AC XY: 14 AN XY: 81876

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 SAS exome AF: 0.0000431

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

Gnomad4 AFR exome AF: 0.000989

Gnomad4 AMR exome AF: 0.000326

Gnomad4 ASJ exome AF: 0.000801

Gnomad4 EAS exome AF: 0.000109

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000171

Gnomad4 OTH exome AF: 0.000246

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

Gnomad4 AFR AF: 0.000759

Gnomad4 AMR AF: 0.00239

Gnomad4 ASJ AF: 0.000871

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000213

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000193

Gnomad4 OTH AF: 0.00240

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000820

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs534696523; hg19: chr16-2154494;