rs1016465177

Positions:

• chr16-2135756-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001009944.3(PKD1):​c.-67C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 961,396 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (12 hom., cov: 31)
  • Exomes 𝑓: 0.00040 (4 hom.)
• Consequence: PKD1 NM_001009944.3 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.315

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 16-2135756-G-A is Benign according to our data. Variant chr16-2135756-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433937.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-2135756-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00465 (682/146822) while in subpopulation AFR AF= 0.016 (656/41024). AF 95% confidence interval is 0.015. There are 12 homozygotes in gnomad4. There are 312 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 682 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD1	NM_001009944.3	c.-67C>T		5_prime_UTR_variant	1/46	ENST00000262304.9
PKD1	NM_000296.4	c.-67C>T		5_prime_UTR_variant	1/46
PKD1	XM_047434208.1	c.-67C>T		5_prime_UTR_variant	1/48
PKD1	XM_047434209.1	c.-67C>T		5_prime_UTR_variant	1/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD1	ENST00000262304.9	c.-67C>T		5_prime_UTR_variant	1/46	1	NM_001009944.3	P5
PKD1	ENST00000423118.5	c.-67C>T		5_prime_UTR_variant	1/46	1		A2

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 682 AN: 146714 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000880

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000455

Gnomad OTH AF: 0.00495

GnomAD4 exome AF: 0.000395 AC: 322 AN: 814574 Hom.: 4 Cov.: 14 AF XY: 0.000364 AC XY: 137 AN XY: 376702

Gnomad4 AFR exome AF: 0.0198

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000134

Gnomad4 OTH exome AF: 0.000561

GnomAD4 genome AF: 0.00465 AC: 682 AN: 146822 Hom.: 12 Cov.: 31 AF XY: 0.00436 AC XY: 312 AN XY: 71480

Gnomad4 AFR AF: 0.0160

Gnomad4 AMR AF: 0.000879

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000455

Gnomad4 OTH AF: 0.00489

Alfa AF: 0.00520 Hom.: 1

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 c.-67C>T variant was identified in the literature in infant with ADPKD with co-occurring certain pathogenic variant PKD1 (c.8362_8363ins34) (Gilbert 2013), and in one individual in our laboratory with pathogenic variant in PKD2 (c.1663C>T (p.Gln555*)), increasing the likelihood that the c.-67C>T variant does not have clinical significance. The variant was also identified in dbSNP (ID: rs1016465177) as "With Likely benign allele", ClinVar (classified as likely benign by one submitter), and ADPKD Mutation Database (as likely neutral). The variant was identified in control databases in 123 of 25272 chromosomes at a frequency of 0.0049 (Genome Aggregation Database Feb 27, 2017), and observed in the following populations: African in 123 of 8194 chromosomes (freq: 0.015), European in 2 of 13610 chromosomes (freq. 0.00014), while not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1016465177; hg19: chr16-2185757;