3-62474171-A-C

Variant names:

• chr3-62474171-A-C
• rs779869722
• NM_003716.4:c.3477+2T>G

Variant summary

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

The NM_003716.4(CADPS):​c.3477+2T>G variant causes a splice donor, intron 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, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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]

ACMG classification

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.000337 AC: 6 AN: 17780 Hom.: 0 Cov.: 0

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 36068 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000101 AC: 4 AN: 394828 Hom.: 0 Cov.: 11 AF XY: 0.0000151 AC XY: 3 AN XY: 199248

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

African (AFR) AF: 0.00 AC: 0 AN: 8526

American (AMR) AF: 0.00 AC: 0 AN: 8490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8894

East Asian (EAS) AF: 0.00 AC: 0 AN: 19490

South Asian (SAS) AF: 0.00 AC: 0 AN: 14232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1922

European-Non Finnish (NFE) AF: 0.0000102 AC: 3 AN: 293398

Other (OTH) AF: 0.0000523 AC: 1 AN: 19130

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0522941), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000337 AC: 6 AN: 17780 Hom.: 0 Cov.: 0 AF XY: 0.000450 AC XY: 4 AN XY: 8896

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

African (AFR) AF: 0.00 AC: 0 AN: 2892

American (AMR) AF: 0.000902 AC: 2 AN: 2218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 546

East Asian (EAS) AF: 0.00 AC: 0 AN: 478

South Asian (SAS) AF: 0.00176 AC: 1 AN: 568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 56

European-Non Finnish (NFE) AF: 0.000329 AC: 3 AN: 9118

Other (OTH) AF: 0.00 AC: 0 AN: 256

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ExAC AF: 0.000170 AC: 20

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	CADPS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.3
GERP RS		6.0
PromoterAI		0.022	Neutral
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs779869722; hg19: chr3-62459846;