3-62474171-A-T

Variant names:

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

Variant summary

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

The NM_003716.4(CADPS):​c.3477+2T>A 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.0071 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CADPS NM_003716.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• 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>A		splice_donor intron	N/A	NP_003707.2
	CADPS	NM_001438347.1		c.3537+2T>A		splice_donor intron	N/A	NP_001425276.1
	CADPS	NM_001438348.1		c.3525+2T>A		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>A		splice_donor intron	N/A	ENSP00000373215.4	Q9ULU8-1
	CADPS	ENST00000612439.4	TSL:1	c.3450+2T>A		splice_donor intron	N/A	ENSP00000484365.1	F1T0E5
	CADPS	ENST00000283269.13	TSL:1	c.3360+2T>A		splice_donor intron	N/A	ENSP00000283269.9	Q9ULU8-3

Frequencies

GnomAD3 genomes AF: 0.00713 AC: 125 AN: 17522 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00948

Gnomad AMI AF: 0.0141

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00183

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.00177

Gnomad FIN AF: 0.00740

Gnomad MID AF: 0.0179

Gnomad NFE AF: 0.00769

Gnomad OTH AF: 0.00407

GnomAD2 exomes AF: 0.00152 AC: 55 AN: 36068 AF XY: 0.00151

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.00239

Gnomad ASJ exome AF: 0.00251

Gnomad EAS exome AF: 0.00190

Gnomad FIN exome AF: 0.00241

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00262

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000655 AC: 258 AN: 394036 Hom.: 0 Cov.: 11 AF XY: 0.000694 AC XY: 138 AN XY: 198820

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

African (AFR) AF: 0.00106 AC: 9 AN: 8500

American (AMR) AF: 0.00118 AC: 10 AN: 8462

Ashkenazi Jewish (ASJ) AF: 0.000788 AC: 7 AN: 8880

East Asian (EAS) AF: 0.000514 AC: 10 AN: 19468

South Asian (SAS) AF: 0.00191 AC: 27 AN: 14130

European-Finnish (FIN) AF: 0.00102 AC: 21 AN: 20680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1918

European-Non Finnish (NFE) AF: 0.000553 AC: 162 AN: 292900

Other (OTH) AF: 0.000628 AC: 12 AN: 19098

⚠️ 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.

GnomAD4 genome AF: 0.00713 AC: 125 AN: 17522 Hom.: 0 Cov.: 0 AF XY: 0.00729 AC XY: 64 AN XY: 8782

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

African (AFR) AF: 0.00945 AC: 27 AN: 2856

American (AMR) AF: 0.00459 AC: 10 AN: 2180

Ashkenazi Jewish (ASJ) AF: 0.00183 AC: 1 AN: 546

East Asian (EAS) AF: 0.00427 AC: 2 AN: 468

South Asian (SAS) AF: 0.00177 AC: 1 AN: 566

European-Finnish (FIN) AF: 0.00740 AC: 11 AN: 1486

Middle Eastern (MID) AF: 0.0208 AC: 1 AN: 48

European-Non Finnish (NFE) AF: 0.00768 AC: 69 AN: 8980

Other (OTH) AF: 0.00400 AC: 1 AN: 250

⚠️ 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.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00180 AC: 211

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
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		0.024	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; COSMIC: COSV51878950; COSMIC: COSV51878950;