16-2089712-C-T

Position:

• chr16-2089712-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.*15G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,566,408 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 34)
  • Exomes 𝑓: 0.012 (174 hom.)
• Consequence: PKD1 NM_001009944.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.541

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=-0.87).
• BP6: Variant 16-2089712-C-T is Benign according to our data. Variant chr16-2089712-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2089712-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0123 (1875/152364) while in subpopulation AMR AF= 0.0188 (288/15304). AF 95% confidence interval is 0.017. There are 18 homozygotes in gnomad4. There are 1049 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1875 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.*15G>A		3_prime_UTR_variant	46/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.*15G>A		3_prime_UTR_variant	46/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.*15G>A		3_prime_UTR_variant	46/46	1		ENSP00000399501	A2
PKD1	ENST00000472577.1	n.955G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1875 AN: 152246 Hom.: 18 Cov.: 34

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0144 AC: 2495 AN: 173144 Hom.: 41 AF XY: 0.0135 AC XY: 1267 AN XY: 93736

Gnomad AFR exome AF: 0.00211

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0470

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00348

Gnomad FIN exome AF: 0.0412

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0124 AC: 17521 AN: 1414044 Hom.: 174 Cov.: 31 AF XY: 0.0121 AC XY: 8442 AN XY: 698910

Gnomad4 AFR exome AF: 0.00192

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.0458

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.00335

Gnomad4 FIN exome AF: 0.0380

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0123 AC: 1875 AN: 152364 Hom.: 18 Cov.: 34 AF XY: 0.0141 AC XY: 1049 AN XY: 74504

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.0188

Gnomad4 ASJ AF: 0.0392

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0407

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0141 Hom.: 4

Bravo AF: 0.0101

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 13, 2020

- -

Autosomal dominant polycystic kidney disease Benign:1

Likely benign, criteria provided, single submitter

research

Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research

Jan 01, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.2
DANN	Benign	0.58
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: rs77566834; hg19: chr16-2139713;