chr3-62465447-C-T

Variant names:

• chr3-62465447-C-T
• rs574220713
• NM_003716.4:c.3556G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003716.4(CADPS):​c.3556G>A​(p.Val1186Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,445,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CADPS NM_003716.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77
• Publications: 4 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13660246).

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.3556G>A	p.Val1186Ile	missense	Exon 26 of 30	NP_003707.2
	CADPS	NM_001438347.1		c.3616G>A	p.Val1206Ile	missense	Exon 27 of 31	NP_001425276.1
	CADPS	NM_001438348.1		c.3604G>A	p.Val1202Ile	missense	Exon 26 of 30	NP_001425277.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CADPS	ENST00000383710.9	TSL:1 MANE Select	c.3556G>A	p.Val1186Ile	missense	Exon 26 of 30	ENSP00000373215.4	Q9ULU8-1
	CADPS	ENST00000612439.4	TSL:1	c.3529G>A	p.Val1177Ile	missense	Exon 24 of 28	ENSP00000484365.1	F1T0E5
	CADPS	ENST00000283269.13	TSL:1	c.3439G>A	p.Val1147Ile	missense	Exon 24 of 28	ENSP00000283269.9	Q9ULU8-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000457 AC: 11 AN: 240616 AF XY: 0.0000385

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.0000180 AC: 26 AN: 1445086 Hom.: 0 Cov.: 28 AF XY: 0.0000167 AC XY: 12 AN XY: 718604

African (AFR) AF: 0.00 AC: 0 AN: 32740

American (AMR) AF: 0.0000236 AC: 1 AN: 42340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25656

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39418

South Asian (SAS) AF: 0.000146 AC: 12 AN: 82402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000906 AC: 10 AN: 1104122

Other (OTH) AF: 0.0000335 AC: 2 AN: 59618

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.0029
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N
PhyloP100		4.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.029
Sift	Benign	0.17	T
Sift4G	Benign	0.25	T
Polyphen		1.0	D
Vest4		0.23
MutPred		0.26		Gain of methylation at K1184 (P = 0.1089)
MVP		0.41
MPC		0.43
ClinPred		0.062	T
GERP RS		4.2
Varity_R		0.049
gMVP		0.033
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs574220713; hg19: chr3-62451122; COSMIC: COSV51902999;