rs142616270

Positions:

• chr16-2092941-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.11156+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,612,910 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (8 hom., cov: 33)
  • Exomes 𝑓: 0.012 (145 hom.)
• Consequence: PKD1 NM_001009944.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.140

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]

PKD1-AS1 (HGNC:56035): (PKD1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-2092941-C-T is Benign according to our data. Variant chr16-2092941-C-T is described in ClinVar as [Benign]. Clinvar id is 256898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2092941-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1553/152324) while in subpopulation NFE AF= 0.0137 (933/68034). AF 95% confidence interval is 0.013. There are 8 homozygotes in gnomad4. There are 775 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1553 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.11156+13G>A		intron_variant		ENST00000262304.9	NP_001009944.3
PKD1-AS1	NR_135175.1	n.232C>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.11156+13G>A		intron_variant		1	NM_001009944.3	ENSP00000262304	P5
PKD1-AS1	ENST00000563284.3	n.123C>T		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1552 AN: 152206 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00824

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.0107 AC: 2672 AN: 250636 Hom.: 30 AF XY: 0.0103 AC XY: 1395 AN XY: 135774

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00839

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.0289

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0124 AC: 18047 AN: 1460586 Hom.: 145 Cov.: 32 AF XY: 0.0121 AC XY: 8756 AN XY: 726580

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00863

Gnomad4 ASJ exome AF: 0.0167

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.0265

Gnomad4 NFE exome AF: 0.0135

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.0102 AC: 1553 AN: 152324 Hom.: 8 Cov.: 33 AF XY: 0.0104 AC XY: 775 AN XY: 74474

Gnomad4 AFR AF: 0.00298

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0289

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0122 Hom.: 3

Bravo AF: 0.00855

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Polycystic kidney disease, adult type Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 04, 2020

- -

Autosomal dominant polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 c.11156+13G>A variant was identified in 10 of 462 proband chromosomes (frequency: 0.022) from individuals or families with ADPKD (Aguiari 2000, Perrichot 1999, Rossetti 2002). The variant was also identified in dbSNP (ID: rs142616270), as “NA”, ADPKD Mutation Database (as likely neutral), in the 1000 Genomes Project in 23 of 5000 chromosomes (frequency: 0.005), NHLBI GO Exome Sequencing Project in 99 of 8600 European American(freq. 0.01) and in 12 of 4396 African American alleles (freq. 0.003), the Exome Aggregation Consortium database (March 14, 2016) in 1179 (10 homozygous) of 120304 chromosomes (freq. 0.01) in the following populations: European in 869 of 65786 chromosomes (freq. 0.01), Finnish in 177 of 6614 chromosomes (freq. 0.03), Latino in 76 of 11556 chromosomes (freq. 0.006), African in 30 of 10312 chromosomes (freq. 0.003), South Asian in 9 of 16510 chromosomes (freq. 0.0005), Other in 18 of 896 chromosomes (freq. 0.02), increasing the likelihood this could be a low frequency benign variant. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In addition, one population study classified the variant as polymorphism since the affected mother carried this nucleotide variation but one of her affected daughters did not share this abnormality (Perrichot 1999). The identification of this variant in an individual by our lab with a co-occurring pathogenic variant (PKD1, c.1583A>G) increases the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

PKD1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.4
DANN	Benign	0.59
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: rs142616270; hg19: chr16-2142942;