Variant 3-62474171-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_003716.4(CADPS):c.3477+2T>G variant causes a splice donor change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CADPS
NM_003716.4 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Variant links:

Genes affected

CADPS (HGNC:1426): (calcium dependent secretion activator) This gene encodes a novel neural/endocrine-specific cytosolic and peripheral membrane protein required for the Ca2+-regulated exocytosis of secretory vesicles. The protein acts at a stage in exocytosis that follows ATP-dependent priming, which involves the essential synthesis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Alternative splicing has been observed at this locus and three variants, encoding distinct isoforms, are described. [provided by RefSeq, Aug 2008]

CADPS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

BayesDel_addAF computational evidence supports a deleterious effect, 0.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CADPS	NM_003716.4 linkuse as main transcript	c.3477+2T>G		splice_donor_variant		ENST00000383710.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CADPS	ENST00000383710.9 linkuse as main transcript	c.3477+2T>G		splice_donor_variant		1	NM_003716.4	P2	Q9ULU8-1

Frequencies

GnomAD3 genomes

AF:

0.000337

AC:

AN:

17780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000902

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00176

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000329

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000101

AC:

AN:

394828

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

199248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000102

Gnomad4 OTH exome

AF:

0.0000523

GnomAD4 genome

AF:

0.000337

AC:

AN:

17780

Hom.:

Cov.:

AF XY:

0.000450

AC XY:

AN XY:

8896

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000902

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00176

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000329

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000170

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CADPS-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2024

The CADPS c.3477+2T>G variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant is predicted to disrupt a canonical splice donor site according to an in silico splicing algorithm (SpliceAI, Jaganathan K, et al. 2019. PubMed ID: 30661751). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.033% of alleles in individuals of African descent in gnomAD. Only a few splice variants have been reported in CADPS with a potential association with disease phenotypes (see, for example, Table 2, Shaheen et al. 2016. PubMed ID: 26633546; Table 1, Bruel et al. 2019. PubMed ID: 31231135; no reports in ClinVar). While we suspect this variant could be pathogenic, at this time the clinical significance of this variant is interpreted as uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D;D

GERP RS

6.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.73

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.73

Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over