16-2115629-T-C

Variant names:

• chr16-2115629-T-C
• rs35929659
• NM_001009944.3:c.1850-4A>G

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.1850-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,579,892 control chromosomes in the GnomAD database, including 31,130 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 0.25 (6595 hom., cov: 32)
  • Exomes 𝑓: 0.17 (24535 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003932
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.944
• Publications: 12 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: Orphanet, ClinGen
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-2115629-T-C is Benign according to our data. Variant chr16-2115629-T-C is described in ClinVar as Benign. ClinVar VariationId is 256929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.472 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.1850-4A>G		splice_region intron	N/A	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.1850-4A>G		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.1850-4A>G		splice_region intron	N/A	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.1850-4A>G		splice_region intron	N/A	ENSP00000399501.1	P98161-3
	PKD1	ENST00000488185.2	TSL:5	c.470+1860A>G		intron	N/A	ENSP00000456672.1	H3BSE9

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38647 AN: 151776 Hom.: 6574 Cov.: 32

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0752

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.250

GnomAD2 exomes AF: 0.155 AC: 34502 AN: 223140 AF XY: 0.150

Gnomad AFR exome AF: 0.474

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.170 AC: 242571 AN: 1427998 Hom.: 24535 Cov.: 33 AF XY: 0.167 AC XY: 118540 AN XY: 710856

African (AFR) AF: 0.486 AC: 15653 AN: 32228

American (AMR) AF: 0.122 AC: 5361 AN: 43984

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6100 AN: 25700

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39620

South Asian (SAS) AF: 0.0748 AC: 6384 AN: 85304

European-Finnish (FIN) AF: 0.181 AC: 8198 AN: 45376

Middle Eastern (MID) AF: 0.233 AC: 950 AN: 4072

European-Non Finnish (NFE) AF: 0.173 AC: 189069 AN: 1092484

Other (OTH) AF: 0.183 AC: 10844 AN: 59230

GnomAD4 genome AF: 0.255 AC: 38711 AN: 151894 Hom.: 6595 Cov.: 32 AF XY: 0.250 AC XY: 18531 AN XY: 74236

African (AFR) AF: 0.478 AC: 19779 AN: 41392

American (AMR) AF: 0.194 AC: 2970 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 831 AN: 3464

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5158

South Asian (SAS) AF: 0.0746 AC: 360 AN: 4826

European-Finnish (FIN) AF: 0.194 AC: 2048 AN: 10584

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 11999 AN: 67884

Other (OTH) AF: 0.247 AC: 521 AN: 2110

Alfa AF: 0.234 Hom.: 1147

Bravo AF: 0.266

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	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	-0.91
CADD	Benign	0.73
DANN	Benign	0.40
PhyloP100		-0.94
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs35929659; hg19: chr16-2165630;