rs867790304

Positions:

• chr16-2135884-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001009944.3(PKD1):​c.-195G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000758 in 216,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: PKD1 NM_001009944.3 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.276

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 16-2135884-C-T is Benign according to our data. Variant chr16-2135884-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 433936.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 143 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.-195G>A		5_prime_UTR_variant	1/46	ENST00000262304.9	NP_001009944.3
PKD1	NM_000296.4	c.-195G>A		5_prime_UTR_variant	1/46		NP_000287.4
PKD1	XM_047434208.1	c.-195G>A		5_prime_UTR_variant	1/48		XP_047290164.1
PKD1	XM_047434209.1	c.-195G>A		5_prime_UTR_variant	1/47		XP_047290165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.-195G>A		5_prime_UTR_variant	1/46	1	NM_001009944.3	ENSP00000262304.4
PKD1	ENST00000423118.5	c.-195G>A		5_prime_UTR_variant	1/46	1		ENSP00000399501.1

Frequencies

GnomAD3 genomes AF: 0.000957 AC: 143 AN: 149394 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00159

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.000631

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00194

GnomAD4 exome AF: 0.000315 AC: 21 AN: 66762 Hom.: 0 Cov.: 0 AF XY: 0.000442 AC XY: 14 AN XY: 31694

Gnomad4 AFR exome AF: 0.000691

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00150

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.00145

GnomAD4 genome AF: 0.000956 AC: 143 AN: 149506 Hom.: 0 Cov.: 31 AF XY: 0.000986 AC XY: 72 AN XY: 73014

Gnomad4 AFR AF: 0.000170

Gnomad4 AMR AF: 0.00159

Gnomad4 ASJ AF: 0.00116

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.000631

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00192

Alfa AF: 0.000810 Hom.: 0

Bravo AF: 0.00125

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1, Promoter region, c.-195G>A variant was not identified in the literature nor was it identified in dbSNP, NHLBI GO Exome Sequencing Project, Exome Aggregation Consortium database (March 14, 2016) Clinvitae, ClinVar, GeneInsight COGR, MutDB, ADPKD Mutation Database PKD1-LOVD and PKD1-LOVD 3.0 databases. To identify conserved putative transcription factor-binding sites, a study cloned and characterized the 5'-flanking regions of the murine and canine Pkd1 genes and performed a multispecies comparison by including sequences from the human and Fugu rubripes orthologues as well as the Pkd2 promoters from mouse and human. Sequence analysis revealed a variety of conserved putative binding sites for transcription factors and no TATA-box element. Nine elements were conserved in the mammalian Pkd1 promoters: AP2, E2F, E-Box, EGRF, ETS, MINI, MZF1, SP1, and ZBP-89. Interestingly, six of these elements were also found in the mammalian Pkd2 promoters. Deletion studies with the mouse Pkd1 promoter showed that a approximately 280 bp fragment is capable of driving luciferase reporter gene expression, whereas reporter constructs containing larger fragments of the Pkd1 promoter showed a lower activity. Furthermore, mutating a potential E2F-binding site within this 280 bp fragment diminished the reporter construct activity, suggesting a role for E2F in regulating cell cycle-dependent expression of the Pkd1 gene. The data define a functional promoter region for Pkd1 and imply that E2F, EGRF, Ets, MZF1, Sp1, and ZBP-89 are potential key regulators of PKD1 and PKD2 in mammals (Lantinga-van Leeuwen 2005). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a Likely Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.96

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: rs867790304; hg19: chr16-2185885;