16-2090261-T-TC

Variant names:

• chr16-2090261-T-TC
• rs547611708
• NM_001009944.3:c.12444+23dupG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.12444+23dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,607,020 control chromosomes in the GnomAD database, including 146 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (4 hom., cov: 34)
  • Exomes 𝑓: 0.012 (142 hom.)
• Consequence: PKD1 NM_001009944.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0930
• Publications: 1 publications found

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]

MIR1225 (HGNC:33931): (microRNA 1225) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 16-2090261-T-TC is Benign according to our data. Variant chr16-2090261-T-TC is described in ClinVar as [Benign]. Clinvar id is 976801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00764 (1156/151254) while in subpopulation NFE AF = 0.0135 (913/67792). AF 95% confidence interval is 0.0127. There are 4 homozygotes in GnomAd4. There are 525 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.12444+23dupG		intron_variant	Intron 45 of 45	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.12444+23dupG		intron_variant	Intron 45 of 45	1	NM_001009944.3	ENSP00000262304.4
PKD1	ENST00000423118.5	c.12441+23dupG		intron_variant	Intron 45 of 45	1		ENSP00000399501.1
MIR1225	ENST00000408729.1	n.23dupG		non_coding_transcript_exon_variant	Exon 1 of 1	6
PKD1	ENST00000472577.1	n.472+23dupG		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1156 AN: 151140 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.00322

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000626

Gnomad FIN AF: 0.00591

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.00433

GnomAD2 exomes AF: 0.00779 AC: 1877 AN: 241054 AF XY: 0.00753

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.000846

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00888

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.00729

GnomAD4 exome AF: 0.0121 AC: 17662 AN: 1455766 Hom.: 142 Cov.: 34 AF XY: 0.0117 AC XY: 8499 AN XY: 723476

African (AFR) AF: 0.00204 AC: 68 AN: 33352

American (AMR) AF: 0.00347 AC: 154 AN: 44320

Ashkenazi Jewish (ASJ) AF: 0.000926 AC: 24 AN: 25904

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39598

South Asian (SAS) AF: 0.000862 AC: 74 AN: 85860

European-Finnish (FIN) AF: 0.00905 AC: 469 AN: 51818

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5752

European-Non Finnish (NFE) AF: 0.0147 AC: 16292 AN: 1109070

Other (OTH) AF: 0.00957 AC: 575 AN: 60092

GnomAD4 genome AF: 0.00764 AC: 1156 AN: 151254 Hom.: 4 Cov.: 34 AF XY: 0.00711 AC XY: 525 AN XY: 73868

African (AFR) AF: 0.00321 AC: 132 AN: 41108

American (AMR) AF: 0.00191 AC: 29 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.000626 AC: 3 AN: 4790

European-Finnish (FIN) AF: 0.00591 AC: 62 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0135 AC: 913 AN: 67792

Other (OTH) AF: 0.00428 AC: 9 AN: 2102

Alfa AF: 0.00331 Hom.: 0

Bravo AF: 0.00738

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant polycystic kidney disease Benign:2

Jan 01, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 11, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MIR1225: BS1, BS2; PKD1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.093
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs547611708; hg19: chr16-2140262;