Genetic Variant CPLX1:p.Gly104Asp (chr4-786595-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006651.4(CPLX1):c.311G>A(p.Gly104Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,611,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CPLX1
NM_006651.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.80

Publications

0 publications found

Variant links:

Genes affected

CPLX1 (HGNC:2309): (complexin 1) Proteins encoded by the complexin/synaphin gene family are cytosolic proteins that function in synaptic vesicle exocytosis. These proteins bind syntaxin, part of the SNAP receptor. The protein product of this gene binds to the SNAP receptor complex and disrupts it, allowing transmitter release. [provided by RefSeq, Jul 2008]

CPLX1 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 63
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial infantile myoclonic epilepsy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CPLX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0438011).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006651.4. 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
	CPLX1	NM_006651.4	MANE Select	c.311G>A	p.Gly104Asp	missense	Exon 4 of 4	NP_006642.1	O14810

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPLX1	ENST00000304062.11	TSL:1 MANE Select	c.311G>A	p.Gly104Asp	missense	Exon 4 of 4	ENSP00000305613.6	O14810
CPLX1	ENST00000892263.1		c.311G>A	p.Gly104Asp	missense	Exon 4 of 4	ENSP00000562322.1
CPLX1	ENST00000892264.1		c.311G>A	p.Gly104Asp	missense	Exon 4 of 4	ENSP00000562323.1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.0000449

AC:

AN:

245244

AF XY:

0.0000524

show subpopulations

Gnomad AFR exome

AF:

0.0000660

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000903

Gnomad OTH exome

AF:

0.000503

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1459786

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.000359

AC:

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

85926

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111248

Other (OTH)

AF:

0.0000664

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

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

AF:

0.000289

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41560

American (AMR)

AF:

0.00248

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67976

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000109

Hom.:

Bravo

AF:

0.000638

ExAC

AF:

0.0000413

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.044

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.5

PhyloP100

5.8

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.93

REVEL

Benign

0.27

Sift

Benign

0.31

Sift4G

Benign

0.46

Polyphen

1.0

Vest4

0.47

MutPred

0.47

Loss of glycosylation at K99 (P = 0.0574)

MVP

0.48

MPC

1.3

ClinPred

0.24

GERP RS

3.6

Varity_R

0.16

gMVP

0.39

Mutation Taster

=46/54

disease causing

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over