rs146430229

Positions:

• chr16-2090595-G-A

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.12139-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000703 in 1,608,366 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00064 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00071 (0 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005694
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.564

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=-0.87).
• BP6: Variant 16-2090595-G-A is Benign according to our data. Variant chr16-2090595-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 256914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2090595-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.12139-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.12139-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001009944.3	P5
PKD1	ENST00000423118.5	c.12136-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A2
PKD1	ENST00000472577.1	n.167-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152194 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000545 AC: 131 AN: 240534 Hom.: 0 AF XY: 0.000676 AC XY: 89 AN XY: 131680

Gnomad AFR exome AF: 0.000319

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000709 AC: 1032 AN: 1456054 Hom.: 0 Cov.: 35 AF XY: 0.000737 AC XY: 534 AN XY: 724484

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000415

Gnomad4 NFE exome AF: 0.000860

Gnomad4 OTH exome AF: 0.000597

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152312 Hom.: 0 Cov.: 34 AF XY: 0.000537 AC XY: 40 AN XY: 74472

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000823 Hom.: 0

Bravo AF: 0.000835

EpiCase AF: 0.00158

EpiControl AF: 0.00220

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	PKD1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2021	- -

Polycystic kidney disease, adult type Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2020	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 c.12139-5C>T variant was not identified in the literature nor was it identified in the COGR, LOVD 3.0, or PKD1-LOVD database. The variant was identified in the following databases: dbSNP (ID: rs146430229) as With Likely benign allele, ClinVar (classified as likely benign by Prevention Genetics), and ADPKD Mutation Database (classified as likely neutral). The variant was identified in control databases in 145 of 267766 chromosomes at a frequency of 0.000542 in the following populations: European in 126 of 122526 chromosomes (freq. 0.001), Latino in 10 of 34254 chromosomes (freq. 0.0003), African in 5 of 23542 chromosomes (freq. 0.0002), Other in 2 of 6342 chromosomes, increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). The c.12139-5C>T 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. However, 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	0.41
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0020
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: rs146430229; hg19: chr16-2140596;