chr16-2106953-C-T

Variant names:

• chr16-2106953-C-T
• rs372745980
• NM_001009944.3:c.7066-5G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.7066-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,584,788 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (7 hom.)
• Consequence: PKD1 NM_001009944.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004365
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.738

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]

MIR6511B1 (HGNC:50228): (microRNA 6511b-1) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-2106953-C-T is Benign according to our data. Variant chr16-2106953-C-T is described in ClinVar as [Benign]. Clinvar id is 256995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2106953-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00667 (1013/151830) while in subpopulation AFR AF = 0.0231 (950/41102). AF 95% confidence interval is 0.0219. There are 13 homozygotes in GnomAd4. There are 507 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1013 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.7066-5G>A		splice_region_variant, intron_variant	Intron 16 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.7066-5G>A		splice_region_variant, intron_variant	Intron 16 of 45	1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1013 AN: 151716 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00120 AC: 274 AN: 227430 AF XY: 0.000927

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.000998

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000281

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000472

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.000473 AC: 678 AN: 1432958 Hom.: 7 Cov.: 29 AF XY: 0.000413 AC XY: 295 AN XY: 714022

Gnomad4 AFR exome AF: 0.0155 AC: 490 AN: 31678

Gnomad4 AMR exome AF: 0.00105 AC: 47 AN: 44640

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26054

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39650

Gnomad4 SAS exome AF: 0.000361 AC: 31 AN: 85990

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 37796

Gnomad4 NFE exome AF: 0.0000363 AC: 40 AN: 1103336

Gnomad4 Remaining exome AF: 0.00106 AC: 63 AN: 59696

GnomAD4 genome AF: 0.00667 AC: 1013 AN: 151830 Hom.: 13 Cov.: 32 AF XY: 0.00683 AC XY: 507 AN XY: 74248

Gnomad4 AFR AF: 0.0231 AC: 0.0231132 AN: 0.0231132

Gnomad4 AMR AF: 0.00281 AC: 0.0028123 AN: 0.0028123

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000579 AC: 0.000579151 AN: 0.000579151

Gnomad4 SAS AF: 0.000207 AC: 0.000207211 AN: 0.000207211

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.000058801 AN: 0.000058801

Gnomad4 OTH AF: 0.00521 AC: 0.00520833 AN: 0.00520833

Alfa AF: 0.000218 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 07, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease, adult type Benign:1

Sep 04, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polycystic kidney disease Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD1 c.7066-5G>A variant was not identified in the literature. The variant was identified in dbSNP (ID: rs372745980) as “With Likely benign allele”, Clinvitae and ClinVar (as likely benign, by Prevention Genetics), ADPKD Mutation Database (as likely neutral), and PKD1-LOVD 3.0 (unclassified, with probability of no functional affect). This variant was identified in the 1000 Genomes Project in 35 of 5008 chromosomes (frequency: 0.007), the NHLBI GO Exome Sequencing Project in 28 of 2604 African American alleles (freq: 0.01), the genome Aggregation Database (beta, October 19th 2016) in 467 (3 homozygous) of 255704 chromosomes (freq. 0.0018), the Exome Aggregation Consortium database (August 8th 2016) in 81 of 93542 chromosomes (freq. 0.00086) specifically in the African population at a greater than 1% frequency: African in 62 of 5588 chromosomes (freq. 0.0111), increasing the likelihood this could be a low frequency benign variant. In addition the variant was identified with a co-occurring pathogenic PKD1 variant (c.7863+1delG) by our laboratory in a patient with ADPKD, increasing the likelihood that the c.7066-5G>A variant does not have clinical significance. This variant was not identified in GeneInsight COGR, COSMIS, MutDB, PKD1-LOVD and HAPMAP databases. The c.7066-5G>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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. -

not provided Benign:1

Apr 30, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PKD1-related disorder Benign:1

Aug 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.47
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00044
dbscSNV1_RF	Benign	0.066
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: rs372745980; hg19: chr16-2156954;