rs115024665

Variant names:

• chr16-2105852-A-G
• rs115024665
• NM_001009944.3:c.7863+13T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.7863+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,594,716 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (24 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (17 hom.)
• Consequence: PKD1 NM_001009944.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.21
• Publications: 1 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=-0.84).
• BP6: Variant 16-2105852-A-G is Benign according to our data. Variant chr16-2105852-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00897 (1366/152280) while in subpopulation AFR AF = 0.0312 (1298/41538). AF 95% confidence interval is 0.0298. There are 24 homozygotes in GnomAd4. There are 665 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AD,AR gene

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.7863+13T>C		intron	N/A	NP_001009944.3	P98161-1
	PKD1	NM_000296.4		c.7863+13T>C		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.7863+13T>C		intron	N/A	ENSP00000262304.4	P98161-1
	PKD1	ENST00000423118.5	TSL:1	c.7863+13T>C		intron	N/A	ENSP00000399501.1	P98161-3
	PKD1	ENST00000486339.6	TSL:5	n.1622T>C		non_coding_transcript_exon	Exon 4 of 14

Frequencies

GnomAD3 genomes AF: 0.00898 AC: 1367 AN: 152162 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00242 AC: 560 AN: 231794 AF XY: 0.00176

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000932

Gnomad OTH exome AF: 0.000847

GnomAD4 exome AF: 0.000930 AC: 1342 AN: 1442436 Hom.: 17 Cov.: 33 AF XY: 0.000829 AC XY: 595 AN XY: 718078

African (AFR) AF: 0.0332 AC: 1109 AN: 33356

American (AMR) AF: 0.00157 AC: 70 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37848

Middle Eastern (MID) AF: 0.000968 AC: 4 AN: 4134

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1110418

Other (OTH) AF: 0.00153 AC: 92 AN: 60036

GnomAD4 genome AF: 0.00897 AC: 1366 AN: 152280 Hom.: 24 Cov.: 32 AF XY: 0.00893 AC XY: 665 AN XY: 74460

African (AFR) AF: 0.0312 AC: 1298 AN: 41538

American (AMR) AF: 0.00242 AC: 37 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68016

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00406 Hom.: 7

Bravo AF: 0.0101

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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	-0.84
CADD	Benign	0.37
DANN	Benign	0.23
PhyloP100		-1.2
PromoterAI		-0.035	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs115024665; hg19: chr16-2155853;