Genetic Variant CPLX1:p.Glu114Gln (chr4-786566-C-G) – 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_006651.4(CPLX1):c.340G>C(p.Glu114Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,642 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. E114K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CPLX1
NM_006651.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.49

Publications

1 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: 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_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.340G>C	p.Glu114Gln	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.340G>C	p.Glu114Gln	missense	Exon 4 of 4	ENSP00000305613.6	O14810
CPLX1	ENST00000892263.1		c.340G>C	p.Glu114Gln	missense	Exon 4 of 4	ENSP00000562322.1
CPLX1	ENST00000892264.1		c.340G>C	p.Glu114Gln	missense	Exon 4 of 4	ENSP00000562323.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000414

AC:

AN:

241680

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000668

Gnomad AMR exome

AF:

0.00

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:

0.00000274

AC:

AN:

1457642

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724838

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33378

American (AMR)

AF:

0.00

AC:

AN:

44268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26022

East Asian (EAS)

AF:

0.00

AC:

AN:

39544

South Asian (SAS)

AF:

0.00

AC:

AN:

85470

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110324

Other (OTH)

AF:

0.00

AC:

AN:

60180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.1

PhyloP100

7.5

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.3

REVEL

Benign

0.27

Sift

Uncertain

0.012

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.31

MutPred

0.70

Gain of glycosylation at S115 (P = 0.0294)

MVP

0.47

MPC

1.1

ClinPred

0.79

GERP RS

3.8

Varity_R

0.23

gMVP

0.48

Mutation Taster

=60/40

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over