16-2090196-T-A

Position:

• chr16-2090196-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000262304.9(PKD1):​c.12445-2A>T variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: PKD1 ENST00000262304.9 splice_acceptor, intron
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.77

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:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2090196-T-A is Pathogenic according to our data. Variant chr16-2090196-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562277.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.12445-2A>T		splice_acceptor_variant, intron_variant		ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.12445-2A>T		splice_acceptor_variant, intron_variant		1	NM_001009944.3	ENSP00000262304.4
PKD1	ENST00000423118.5	c.12442-2A>T		splice_acceptor_variant, intron_variant		1		ENSP00000399501.1
MIR1225	ENST00000408729.1	n.89A>T		splice_region_variant, non_coding_transcript_exon_variant	1/1	6
PKD1	ENST00000472577.1	n.473-2A>T		splice_acceptor_variant, intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Gharavi Laboratory, Columbia University

Sep 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	34
DANN	Benign	0.96
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.87		Position offset: -15
DS_AL_spliceai		0.98		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555444334; hg19: chr16-2140197;