16-2106953-C-T

Position:

• chr16-2106953-C-T

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004365
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1013 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.7066-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.7066-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001009944.3	ENSP00000262304	P5

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

GnomAD3 exomes AF: 0.00120 AC: 274 AN: 227430 Hom.: 2 AF XY: 0.000927 AC XY: 117 AN XY: 126216

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 SAS exome AF: 0.000265

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

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000361

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000363

Gnomad4 OTH exome AF: 0.00106

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

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.000218 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 04, 2018

- -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 30, 2020

- -

PKD1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 05, 2019

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

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;