rs114846412

Variant names:

• chr16-2113297-G-A
• rs114846412
• NM_001009944.3:c.2854-5C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2113297-G-A
• chr16-2113297-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001009944.3(PKD1):​c.2854-5C>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 0.00589 in 1,594,686 control chromosomes in the GnomAD database, including 507 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (268 hom., cov: 29)
  • Exomes 𝑓: 0.0034 (239 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, intron
• Scores: Splicing: ADA: 0.00004595
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.06
• Publications: 5 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

ENSG00000261240 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-2113297-G-A is Benign according to our data. Variant chr16-2113297-G-A is described in ClinVar as Benign. ClinVar VariationId is 256938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009944.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.2854-5C>T		splice_region intron	N/A	NP_001009944.3
	PKD1	NM_000296.4		c.2854-5C>T		splice_region intron	N/A	NP_000287.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.2854-5C>T		splice_region intron	N/A	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.2854-5C>T		splice_region intron	N/A	ENSP00000399501.1
	PKD1	ENST00000488185.2	TSL:5	c.470+4192C>T		intron	N/A	ENSP00000456672.1

Frequencies

GnomAD3 genomes AF: 0.0299 AC: 4532 AN: 151614 Hom.: 268 Cov.: 29

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000418

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.00880 AC: 1825 AN: 207342 AF XY: 0.00629

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.00623

Gnomad ASJ exome AF: 0.00106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000104

Gnomad NFE exome AF: 0.000512

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00336 AC: 4853 AN: 1442956 Hom.: 239 Cov.: 31 AF XY: 0.00286 AC XY: 2052 AN XY: 718284

African (AFR) AF: 0.107 AC: 3581 AN: 33360

American (AMR) AF: 0.00729 AC: 326 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86142

European-Finnish (FIN) AF: 0.0000528 AC: 2 AN: 37892

Middle Eastern (MID) AF: 0.00557 AC: 23 AN: 4132

European-Non Finnish (NFE) AF: 0.000359 AC: 399 AN: 1110834

Other (OTH) AF: 0.00797 AC: 479 AN: 60074

GnomAD4 genome AF: 0.0299 AC: 4537 AN: 151730 Hom.: 268 Cov.: 29 AF XY: 0.0285 AC XY: 2114 AN XY: 74168

African (AFR) AF: 0.103 AC: 4266 AN: 41252

American (AMR) AF: 0.0103 AC: 157 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4782

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10578

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 67940

Other (OTH) AF: 0.0260 AC: 55 AN: 2112

Alfa AF: 0.00189 Hom.: 3

Bravo AF: 0.0341

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease, adult type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.056
DANN	Benign	0.59
PhyloP100		-3.1
PromoterAI		-0.0088	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs114846412; hg19: chr16-2163298;