rs2369068

chr16-2112886-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001009944.3(PKD1):c.3063T>C(p.Gly1021=) 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 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.34

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 256942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2112886-A-G is described in Lovd as [Likely_benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.3063T>C	p.Gly1021=	synonymous_variant	13/46	ENST00000262304.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.3063T>C	p.Gly1021=	synonymous_variant	13/46	1	NM_001009944.3	P5
	ENST00000568795.1	n.161-161A>G		intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.105 AC: 25957 AN: 246982 Hom.: 2781 AF XY: 0.0966 AC XY: 12964 AN XY: 134200

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 SAS exome AF: 0.0294

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

Gnomad4 AFR exome AF: 0.473

Gnomad4 AMR exome AF: 0.0900

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0321

Gnomad4 FIN exome AF: 0.0676

Gnomad4 NFE exome AF: 0.0991

Gnomad4 OTH exome AF: 0.119

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

Gnomad4 AFR AF: 0.459

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0281

Gnomad4 FIN AF: 0.0762

Gnomad4 NFE AF: 0.0993

Gnomad4 OTH AF: 0.190

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 07, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The c.3063T>C, p.Gly1021Gly variant was identified in 11% of 13209 control alleles in the Exome Aggregation Consortium (March 14, 2016). According to ACMG guidelines for variant classification based on allele frequency, category BA1, this variant is considered benign and has not been further reviewed (Richards 2015). -

Autosomal dominant polycystic kidney disease Benign:1

Benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2019

This variant is associated with the following publications: (PMID: 10364515) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	2.6
Dann	Benign	0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs2369068; hg19: chr16-2162887;