chr16-2102387-C-G

Position:

• chr16-2102387-C-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.9195G>C​(p.Val3065=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,555,570 control chromosomes in the GnomAD database, including 27,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6325 hom., cov: 33)
  • Exomes 𝑓: 0.16 (21588 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.786

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-2102387-C-G is Benign according to our data. Variant chr16-2102387-C-G is described in ClinVar as [Benign]. Clinvar id is 257039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.786 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.9195G>C	p.Val3065=	synonymous_variant	25/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.9195G>C	p.Val3065=	synonymous_variant	25/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37356 AN: 151642 Hom.: 6306 Cov.: 33

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0703

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.232

GnomAD3 exomes AF: 0.156 AC: 24792 AN: 158570 Hom.: 2758 AF XY: 0.149 AC XY: 12566 AN XY: 84292

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.000260

Gnomad SAS exome AF: 0.0731

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.164 AC: 229811 AN: 1403812 Hom.: 21588 Cov.: 35 AF XY: 0.160 AC XY: 111141 AN XY: 693440

Gnomad4 AFR exome AF: 0.495

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.236

Gnomad4 EAS exome AF: 0.000436

Gnomad4 SAS exome AF: 0.0747

Gnomad4 FIN exome AF: 0.181

Gnomad4 NFE exome AF: 0.164

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.247 AC: 37419 AN: 151758 Hom.: 6325 Cov.: 33 AF XY: 0.241 AC XY: 17871 AN XY: 74226

Gnomad4 AFR AF: 0.482

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.232

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0698

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.230

Alfa AF: 0.156 Hom.: 719

Bravo AF: 0.259

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	This variant is associated with the following publications: (PMID: 15772804, 10854095, 18837007, 22608885, 24374109) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 08, 2020

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.55
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs9935834; hg19: chr16-2152388; COSMIC: COSV51923518; COSMIC: COSV51923518;