7-122387076-C-T

Position:

• chr7-122387076-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 715236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CADPS2	NM_017954.11	c.3262G>A	p.Asp1088Asn	missense_variant	24/30	ENST00000449022.7	NP_060424.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CADPS2	ENST00000449022.7	c.3262G>A	p.Asp1088Asn	missense_variant	24/30	5	NM_017954.11	ENSP00000398481
	ENST00000630777.2	n.162+32660C>T		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.00196 AC: 344 AN: 175128 Hom.: 4 AF XY: 0.00200 AC XY: 185 AN XY: 92396

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 SAS exome AF: 0.000631

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

Gnomad4 AFR exome AF: 0.000619

Gnomad4 AMR exome AF: 0.000701

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000673

Gnomad4 FIN exome AF: 0.000460

Gnomad4 NFE exome AF: 0.00527

Gnomad4 OTH exome AF: 0.00373

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

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00418

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00359 Hom.: 2

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

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

CADPS2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.012	T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.6	.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.8	.;D;.;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	.;D;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		1.0	.;.;.;D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs76528953; hg19: chr7-122027130;