16-2091607-G-T

Variant names:

• chr16-2091607-G-T
• rs377419559
• NM_001009944.3:c.11538-10C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001009944.3(PKD1):​c.11538-10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,561,070 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 Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: PKD1 NM_001009944.3 intron
• Scores: Splicing: ADA: 0.003918
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.295
• 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-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.11538-10C>A		intron_variant	Intron 41 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.11538-10C>A		intron_variant	Intron 41 of 45	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000116 AC: 20 AN: 172080 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000240 AC: 338 AN: 1408954 Hom.: 0 Cov.: 32 AF XY: 0.000249 AC XY: 174 AN XY: 697572

African (AFR) AF: 0.0000307 AC: 1 AN: 32588

American (AMR) AF: 0.00 AC: 0 AN: 39552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24860

East Asian (EAS) AF: 0.00 AC: 0 AN: 37944

South Asian (SAS) AF: 0.00 AC: 0 AN: 81196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4948

European-Non Finnish (NFE) AF: 0.000293 AC: 321 AN: 1093934

Other (OTH) AF: 0.000273 AC: 16 AN: 58624

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152116 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74310

African (AFR) AF: 0.000121 AC: 5 AN: 41432

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67976

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000121

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Polycystic kidney disease Uncertain:1

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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.11538-10C>A variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, or PKD1-LOVD databases. The variant was identified in dbSNP (ID: rs377419559) as "With Likely benign allele" however this is in reference to the ClinVar submission of the PKD1, c.11538-10C>T variant which is classified as likely benign by Prevention Genetic. The c.11538-10C>A variant was also identified in the ADPKD Mutation Database (1 entry classified as likely pathogenic by Athena Diagnostics). The variant was identified in control databases in 22 of 199024 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 18182 chromosomes (freq: 0.00006), Latino in 1 of 28462 chromosomes (freq: 0.00004), European Non-Finnish in 20 of 88366 chromosomes (freq: 0.0002), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.11538-10C>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.4
DANN	Benign	0.73
PhyloP100		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0039
dbscSNV1_RF	Benign	0.072
SpliceAI score (max)		0.17		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: rs377419559; hg19: chr16-2141608;