rs115772084

Positions:

• chr16-2106612-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001009944.3(PKD1):​c.7275C>T​(p.Gly2425=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,598,402 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (10 hom.)
• Consequence: PKD1 NM_001009944.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.643

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=-0.57).
• BP6: Variant 16-2106612-G-A is Benign according to our data. Variant chr16-2106612-G-A is described in ClinVar as [Benign]. Clinvar id is 256999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.643 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00831 (1265/152290) while in subpopulation AFR AF= 0.0273 (1133/41554). AF 95% confidence interval is 0.0259. There are 19 homozygotes in gnomad4. There are 629 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1265 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.7275C>T	p.Gly2425=	synonymous_variant	18/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.7275C>T	p.Gly2425=	synonymous_variant	18/46	1	NM_001009944.3	ENSP00000262304	P5

Frequencies

GnomAD3 genomes AF: 0.00825 AC: 1255 AN: 152170 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00238 AC: 556 AN: 234040 Hom.: 6 AF XY: 0.00193 AC XY: 249 AN XY: 128754

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00539

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000157

Gnomad OTH exome AF: 0.00187

GnomAD4 exome AF: 0.000950 AC: 1374 AN: 1446112 Hom.: 10 Cov.: 33 AF XY: 0.000874 AC XY: 629 AN XY: 719966

Gnomad4 AFR exome AF: 0.0271

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.00709

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.00223

GnomAD4 genome AF: 0.00831 AC: 1265 AN: 152290 Hom.: 19 Cov.: 32 AF XY: 0.00845 AC XY: 629 AN XY: 74450

Gnomad4 AFR AF: 0.0273

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00563 Hom.: 2

Bravo AF: 0.00927

EpiCase AF: 0.000382

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2019

- -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Gly2425= variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from individuals or families with Autosomal Dominant PKD (Garcia-Gonzalez 2007). The variant was also identified in dbSNP (ID: rs115772084) as “With Likely benign allele”, ClinVar (as likely benign by Prevention Genetics which was then changed to uncertain significance in 2016), and ADPKD Mutation Database (as indeterminate). The variant was not identified in LOVD 3.0, or PKD1-LOVD. The variant was identified in control databases in 779 of 261798 chromosomes (6 homozygous) at a frequency of 0.002976 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 640 of 23178 chromosomes (freq: 0.02761), Other in 9 of 6270 chromosomes (freq: 0.001435), Latino in 57 of 34144 chromosomes (freq: 0.001669), European (Non-Finnish) in 18 of 122112 chromosomes (freq: 0.000147), Ashkenazi Jewish in 55 of 9964 chromosomes (freq: 0.00552), while the variant was not observed in the East Asian, European Finnish, and South Asian populations. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Gly2425= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.3
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs115772084; hg19: chr16-2156613;