rs2369068

Variant names:

• chr16-2112886-A-G
• rs2369068
• NM_001009944.3:c.3063T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000262304.9(PKD1):​c.3063T>C​(p.Gly1021Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,606,556 control chromosomes in the GnomAD database, including 15,703 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (5073 hom., cov: 33)
  • Exomes 𝑓: 0.10 (10630 hom.)
• Consequence: PKD1 ENST00000262304.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.34
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 16-2112886-A-G is Benign according to our data. Variant chr16-2112886-A-G is described in ClinVar as Benign. ClinVar VariationId is 256942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000262304.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	NM_001009944.3	MANE Select	c.3063T>C	p.Gly1021Gly	synonymous	Exon 13 of 46	NP_001009944.3
	PKD1	NM_000296.4		c.3063T>C	p.Gly1021Gly	synonymous	Exon 13 of 46	NP_000287.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD1	ENST00000262304.9	TSL:1 MANE Select	c.3063T>C	p.Gly1021Gly	synonymous	Exon 13 of 46	ENSP00000262304.4
	PKD1	ENST00000423118.5	TSL:1	c.3063T>C	p.Gly1021Gly	synonymous	Exon 13 of 46	ENSP00000399501.1
	PKD1	ENST00000415938.7	TSL:5	n.78T>C		non_coding_transcript_exon	Exon 1 of 17

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29808 AN: 151862 Hom.: 5057 Cov.: 33

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0285

Gnomad FIN AF: 0.0762

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.0993

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.105 AC: 25957 AN: 246982 AF XY: 0.0966

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.0819

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0699

Gnomad NFE exome AF: 0.0991

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.102 AC: 147802 AN: 1454576 Hom.: 10630 Cov.: 35 AF XY: 0.0988 AC XY: 71494 AN XY: 723778

African (AFR) AF: 0.473 AC: 15800 AN: 33388

American (AMR) AF: 0.0900 AC: 4025 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3936 AN: 26126

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39694

South Asian (SAS) AF: 0.0321 AC: 2769 AN: 86160

European-Finnish (FIN) AF: 0.0676 AC: 3292 AN: 48664

Middle Eastern (MID) AF: 0.176 AC: 727 AN: 4136

European-Non Finnish (NFE) AF: 0.0991 AC: 110112 AN: 1111546

Other (OTH) AF: 0.119 AC: 7133 AN: 60154

GnomAD4 genome AF: 0.197 AC: 29867 AN: 151980 Hom.: 5073 Cov.: 33 AF XY: 0.189 AC XY: 14023 AN XY: 74292

African (AFR) AF: 0.459 AC: 18981 AN: 41396

American (AMR) AF: 0.135 AC: 2070 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 552 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0281 AC: 135 AN: 4804

European-Finnish (FIN) AF: 0.0762 AC: 805 AN: 10568

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.0993 AC: 6750 AN: 67964

Other (OTH) AF: 0.190 AC: 402 AN: 2114

Alfa AF: 0.140 Hom.: 559

Bravo AF: 0.215

Asia WGS AF: 0.0440 AC: 156 AN: 3478

EpiCase AF: 0.111

EpiControl AF: 0.114

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)
-	-	2	Polycystic kidney disease, adult type (2)
-	-	1	Autosomal dominant polycystic kidney disease (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.6
DANN	Benign	0.76
PhyloP100		2.3
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=98/2	polymorphism (auto)

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: rs2369068; hg19: chr16-2162887;