chr16-2114928-G-A

Variant names:

• chr16-2114928-G-A
• rs1295368570
• NM_001009944.3:c.2098-3C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001009944.3(PKD1):​c.2098-3C>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 0.0000268 in 1,529,990 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002725
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.443
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-2114928-G-A is Benign according to our data. Variant chr16-2114928-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433950.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.2098-3C>T		splice_region_variant, intron_variant	Intron 10 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.2098-3C>T		splice_region_variant, intron_variant	Intron 10 of 45	1	NM_001009944.3	ENSP00000262304.4
PKD1	ENST00000423118.5	c.2098-3C>T		splice_region_variant, intron_variant	Intron 10 of 45	1		ENSP00000399501.1
PKD1	ENST00000488185.2	c.470+2561C>T		intron_variant	Intron 2 of 4	5		ENSP00000456672.1
PKD1	ENST00000568591.5	n.*426-3C>T		splice_region_variant, intron_variant	Intron 6 of 11	2		ENSP00000457162.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000391 AC: 4 AN: 102202 AF XY: 0.0000188

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000254

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000261 AC: 36 AN: 1377740 Hom.: 0 Cov.: 30 AF XY: 0.0000265 AC XY: 18 AN XY: 680526

African (AFR) AF: 0.0000317 AC: 1 AN: 31520

American (AMR) AF: 0.00 AC: 0 AN: 36050

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.0000555 AC: 2 AN: 36046

South Asian (SAS) AF: 0.00 AC: 0 AN: 79134

European-Finnish (FIN) AF: 0.0000295 AC: 1 AN: 33952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4056

European-Non Finnish (NFE) AF: 0.0000298 AC: 32 AN: 1074228

Other (OTH) AF: 0.00 AC: 0 AN: 57604

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74386

African (AFR) AF: 0.0000482 AC: 2 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 c.2098-3C>T variant was not identified in the literature nor was it identified in dbSNP, Clinvitae database, the ClinVar database, GeneInsight COGR database, ADPKD Mutation Database, PKD1-LOVD, PKD1-LOVD 3.0, 1000 Genomes Project, NHLBI GO Exome Sequencing Project (ESP), and the Exome Aggregation Consortium database (March 14, 2016). The c.2098-3C>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. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site; however, HumanSpliceFinder, MaxEntScan and GeneSplicer predict the loss of a 5' cryptic donor splice site at this position and we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site. 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. In addition this variant was identified co-occurring with a pathogenic PKD1 variant (PKD1, EXON43, c.11798_11810del, p.Leu3933ArgfsX8) in a patient with a clinical diagnosis of ADPKD . This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.80
PhyloP100		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.070		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: rs1295368570; hg19: chr16-2164929;