16-2100322-A-G

Variant names:

• chr16-2100322-A-G
• rs11248911
• NM_001009944.3:c.9569-13T>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.9569-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0735 in 1,575,576 control chromosomes in the GnomAD database, including 9,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (3570 hom., cov: 33)
  • Exomes 𝑓: 0.064 (5812 hom.)
• Consequence: PKD1 NM_001009944.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.04
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-2100322-A-G is Benign according to our data. Variant chr16-2100322-A-G is described in ClinVar as Benign. ClinVar VariationId is 257043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 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.9569-13T>C		intron	N/A	NP_001009944.3
	PKD1	NM_000296.4		c.9569-13T>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.9569-13T>C		intron	N/A	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.9569-13T>C		intron	N/A	ENSP00000399501.1
	PKD1	ENST00000480227.5	TSL:1	n.1306-13T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24303 AN: 152130 Hom.: 3550 Cov.: 33

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0950

Gnomad ASJ AF: 0.0882

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0470

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0679

Gnomad OTH AF: 0.140

GnomAD2 exomes AF: 0.0388 AC: 8895 AN: 229308 AF XY: 0.0336

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.0277

Gnomad ASJ exome AF: 0.0354

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0564

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0345

GnomAD4 exome AF: 0.0642 AC: 91385 AN: 1423328 Hom.: 5812 Cov.: 32 AF XY: 0.0631 AC XY: 44740 AN XY: 709398

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.379 AC: 11459 AN: 30274

American (AMR) AF: 0.0499 AC: 2208 AN: 44258

Ashkenazi Jewish (ASJ) AF: 0.0912 AC: 2341 AN: 25670

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39692

South Asian (SAS) AF: 0.0422 AC: 3610 AN: 85494

European-Finnish (FIN) AF: 0.111 AC: 5767 AN: 52186

Middle Eastern (MID) AF: 0.0696 AC: 282 AN: 4052

European-Non Finnish (NFE) AF: 0.0565 AC: 61137 AN: 1082756

Other (OTH) AF: 0.0775 AC: 4567 AN: 58946

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.160 AC: 24363 AN: 152248 Hom.: 3570 Cov.: 33 AF XY: 0.159 AC XY: 11810 AN XY: 74444

African (AFR) AF: 0.390 AC: 16210 AN: 41536

American (AMR) AF: 0.0949 AC: 1452 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0882 AC: 306 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5172

South Asian (SAS) AF: 0.0464 AC: 224 AN: 4826

European-Finnish (FIN) AF: 0.115 AC: 1224 AN: 10614

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0679 AC: 4615 AN: 68004

Other (OTH) AF: 0.138 AC: 292 AN: 2114

Alfa AF: 0.0587 Hom.: 106

Bravo AF: 0.167

ClinVar

ClinVar submissions as Germline

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	-0.92
CADD	Benign	0.045
DANN	Benign	0.28
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11248911; hg19: chr16-2150323;