rs7192711

Positions:

• chr16-2093752-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000262304.9(PKD1):​c.10822-14C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00621 in 1,570,898 control chromosomes in the GnomAD database, including 483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (275 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (208 hom.)
• Consequence: PKD1 ENST00000262304.9 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.405

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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-2093752-G-A is Benign according to our data. Variant chr16-2093752-G-A is described in ClinVar as [Benign]. Clinvar id is 256896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2093752-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.10822-14C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262304.9	NP_001009944.3
PKD1-AS1	NR_135175.1	n.303+740G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.10822-14C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001009944.3	ENSP00000262304	P5
PKD1-AS1	ENST00000563284.3	n.194+740G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4864 AN: 152146 Hom.: 274 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.00815 AC: 1467 AN: 179918 Hom.: 69 AF XY: 0.00640 AC XY: 626 AN XY: 97758

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.00644

Gnomad ASJ exome AF: 0.00572

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.00623

GnomAD4 exome AF: 0.00343 AC: 4865 AN: 1418634 Hom.: 208 Cov.: 32 AF XY: 0.00300 AC XY: 2107 AN XY: 702524

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00676

Gnomad4 ASJ exome AF: 0.00717

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000195

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000333

Gnomad4 OTH exome AF: 0.00790

GnomAD4 genome AF: 0.0321 AC: 4885 AN: 152264 Hom.: 275 Cov.: 33 AF XY: 0.0316 AC XY: 2356 AN XY: 74460

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00817 Hom.: 48

Bravo AF: 0.0363

Asia WGS AF: 0.00433 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 28, 2020

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Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 c.10822-14C>T variant was identified in 3 of 460 proband chromosomes (frequency: 0.007) from American individuals or families with ADPKD (Rossetti 2012). The variant was also identified in dbSNP (ID: rs7192711) as “With Benign allele”, the ADPKD Mutation Database (classification likely neutral), the 1000 Genomes Project in 165 of 5015 chromosomes (frequency: 0.03), HAPMAP-YRI in 26 of 226 chromosomes (frequency: 0.115), HAPMAP-ASW in 12 of 98 chromosomes (frequency: 0.122), HAPMAP-LWK in 22 of 189 chromosomes (frequency: 0.122), the NHLBI GO Exome Sequencing Project in 8 of 8552 European American alleles (frequency: 0.0009) and in 453 of 4362 African American alleles (frequency: 0.1), and in the Exome Aggregation Consortium database (August 8, 2016) in 531 of 33314 chromosomes (29 homozgyous) (frequency: 0.02) in the following populations: African in 466 (29 homozygotes) of 3264 chromosomes (frequency: 0.1), Latino in 31 of 2608 chromosomes (frequency: 0.01), Other in 2 of 280 chromosomes (frequency: 0.007), European (Non-Finnish) in 110 of 64720 chromosomes (frequency: 0.002), and South Asian in 1 of 9322 chromosomes (frequency: 0.0001), but was not seen in East Asian and Finnish and populations. The variant was also identified in Clinvitae (classification benign), ClinVar (classification benign, submitter Prevention Genetics), but was not in GeneInsight-COGR, PKD1-LOVD, and PKD1-LOVD 3.0. The variant was identified by our laboratory in 1 individual with ADPKD, co-occurring with a pathogenic PKD1 variant (c.12178C>T, p.Gln4060X), increasing the likelihood that the variant does not have clinical significance. The c.10822-14C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. In addition, five of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.3
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs7192711; hg19: chr16-2143753;