rs76528953

Variant names:

• chr7-122387076-C-T
• rs76528953
• NM_017954.11:c.3262G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017954.11(CADPS2):​c.3262G>A​(p.Asp1088Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,561,438 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (21 hom.)
• Consequence: CADPS2 NM_017954.11 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.57
• Publications: 7 publications found

Genes affected

CADPS2 (HGNC:16018): (calcium dependent secretion activator 2) This gene encodes a member of the calcium-dependent activator of secretion (CAPS) protein family, which are calcium binding proteins that regulate the exocytosis of synaptic and dense-core vesicles in neurons and neuroendocrine cells. Mutations in this gene may contribute to autism susceptibility. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2009]

ENSG00000240499 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012353718).
• BP6: Variant 7-122387076-C-T is Benign according to our data. Variant chr7-122387076-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 715236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017954.11. 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
	CADPS2	NM_017954.11	MANE Select	c.3262G>A	p.Asp1088Asn	missense	Exon 24 of 30	NP_060424.9
	CADPS2	NM_001363389.2		c.3283G>A	p.Asp1095Asn	missense	Exon 25 of 32	NP_001350318.1
	CADPS2	NM_001363390.2		c.3283G>A	p.Asp1095Asn	missense	Exon 25 of 31	NP_001350319.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CADPS2	ENST00000449022.7	TSL:5 MANE Select	c.3262G>A	p.Asp1088Asn	missense	Exon 24 of 30	ENSP00000398481.2	Q86UW7-1
	CADPS2	ENST00000412584.6	TSL:1	c.3124G>A	p.Asp1042Asn	missense	Exon 21 of 28	ENSP00000400401.2	Q86UW7-2
	CADPS2	ENST00000951082.1		c.3265G>A	p.Asp1089Asn	missense	Exon 23 of 30	ENSP00000621141.1

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 342 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00418

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00196 AC: 344 AN: 175128 AF XY: 0.00200

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000649

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000113

Gnomad NFE exome AF: 0.00417

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00429 AC: 6044 AN: 1409250 Hom.: 21 Cov.: 30 AF XY: 0.00428 AC XY: 2980 AN XY: 695824

African (AFR) AF: 0.000619 AC: 20 AN: 32320

American (AMR) AF: 0.000701 AC: 26 AN: 37076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25352

East Asian (EAS) AF: 0.00 AC: 0 AN: 37166

South Asian (SAS) AF: 0.000673 AC: 54 AN: 80188

European-Finnish (FIN) AF: 0.000460 AC: 23 AN: 49996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00527 AC: 5703 AN: 1082988

Other (OTH) AF: 0.00373 AC: 218 AN: 58462

GnomAD4 genome AF: 0.00225 AC: 342 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74416

African (AFR) AF: 0.000842 AC: 35 AN: 41558

American (AMR) AF: 0.000786 AC: 12 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00418 AC: 284 AN: 67980

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00341 Hom.: 6

Bravo AF: 0.00239

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000506 AC: 2

ESP6500EA AF: 0.00338 AC: 28

ExAC AF: 0.00147 AC: 173

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CADPS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.86
MVP		0.69
MPC		0.18
ClinPred		0.065	T
GERP RS		4.9
Varity_R		0.60
gMVP		0.41
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs76528953; hg19: chr7-122027130;