Genetic Variant CADPS:c.3477+2T>C (chr3-62474171-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_003716.4(CADPS):c.3477+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CADPS
NM_003716.4 splice_donor, intron

Scores

Splicing: ADA: 0.9923

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.32

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003716.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CADPS	NM_003716.4	MANE Select	c.3477+2T>C	splice_donor intron	N/A	NP_003707.2
CADPS	NM_001438347.1		c.3537+2T>C	splice_donor intron	N/A	NP_001425276.1
CADPS	NM_001438348.1		c.3525+2T>C	splice_donor intron	N/A	NP_001425277.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CADPS	ENST00000383710.9	TSL:1 MANE Select	c.3477+2T>C	splice_donor intron	N/A	ENSP00000373215.4	Q9ULU8-1
CADPS	ENST00000612439.4	TSL:1	c.3450+2T>C	splice_donor intron	N/A	ENSP00000484365.1	F1T0E5
CADPS	ENST00000283269.13	TSL:1	c.3360+2T>C	splice_donor intron	N/A	ENSP00000283269.9	Q9ULU8-3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

17802

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000507

AC:

AN:

394842

Hom.:

Cov.:

AF XY:

0.0000100

AC XY:

AN XY:

199260

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

8526

American (AMR)

AF:

0.00

AC:

AN:

8490

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8894

East Asian (EAS)

AF:

0.00

AC:

AN:

19490

South Asian (SAS)

AF:

0.00

AC:

AN:

14234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20748

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1928

European-Non Finnish (NFE)

AF:

0.00000682

AC:

AN:

293402

Other (OTH)

AF:

0.00

AC:

AN:

19130

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

17802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

8908

African (AFR)

AF:

0.00

AC:

AN:

2898

American (AMR)

AF:

0.00

AC:

AN:

2220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

546

East Asian (EAS)

AF:

0.00

AC:

AN:

478

South Asian (SAS)

AF:

0.00

AC:

AN:

568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

9132

Other (OTH)

AF:

0.00

AC:

AN:

256

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

PhyloP100

9.3

GERP RS

6.0

PromoterAI

0.0084

Neutral

(source)

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.69

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over