Genetic Variant CADPS2:p.Met1180Lys (chr7-122345647-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_017954.11(CADPS2):c.3539T>A(p.Met1180Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,076 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1180T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CADPS2
NM_017954.11 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.88

Publications

2 publications found

Variant links:

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]

CADPS2 links:

ENSG00000240499 (HGNC:):

ENSG00000240499 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CADPS2	NM_017954.11	MANE Select	c.3539T>A	p.Met1180Lys	missense	Exon 28 of 30	NP_060424.9
CADPS2	NM_001363389.2		c.3575T>A	p.Met1192Lys	missense	Exon 30 of 32	NP_001350318.1
CADPS2	NM_001363390.2		c.3560T>A	p.Met1187Lys	missense	Exon 29 of 31	NP_001350319.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CADPS2	ENST00000449022.7	TSL:5 MANE Select	c.3539T>A	p.Met1180Lys	missense	Exon 28 of 30	ENSP00000398481.2	Q86UW7-1
CADPS2	ENST00000412584.6	TSL:1	c.3416T>A	p.Met1139Lys	missense	Exon 26 of 28	ENSP00000400401.2	Q86UW7-2
CADPS2	ENST00000951082.1		c.3557T>A	p.Met1186Lys	missense	Exon 28 of 30	ENSP00000621141.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248700

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

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

AF:

6.84e-7

AC:

AN:

1461076

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.0000224

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111488

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.011

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0091

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

2.9

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.38

REVEL

Benign

0.12

Sift

Benign

0.24

Sift4G

Benign

0.68

Polyphen

0.015

Vest4

0.78

MVP

0.30

MPC

0.028

ClinPred

0.25

GERP RS

6.1

Varity_R

0.31

gMVP

0.60

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over