rs371709824

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_006651.4(CPLX1):c.382C>A(p.Leu128Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,599,682 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

CPLX1
NM_006651.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 7.50

Publications

4 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;

PP5

Variant 4-786524-G-T is Pathogenic according to our data. Variant chr4-786524-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 523650.

BP4

Computational evidence support a benign effect (MetaRNN=0.054480672). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLX1	NM_006651.4 link	c.382C>A	p.Leu128Met	missense_variant	Exon 4 of 4	ENST00000304062.11	NP_006642.1	O14810
CPLX1	XM_011513391.2 link	c.337C>A	p.Leu113Met	missense_variant	Exon 3 of 3		XP_011511693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPLX1	ENST00000304062.11 link	c.382C>A	p.Leu128Met	missense_variant	Exon 4 of 4	1	NM_006651.4	ENSP00000305613.6	O14810
CPLX1	ENST00000505203.1 link	c.319C>A	p.Leu107Met	missense_variant	Exon 5 of 5	2		ENSP00000425960.1	D6RI11
CPLX1	ENST00000506404.1 link	n.435C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
CPLX1	ENST00000504062.1 link	c.*7C>A		downstream_gene_variant		3		ENSP00000421947.1	D6RAG3

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000923

AC:

AN:

227544

AF XY:

0.000113

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00210

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000984

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000712

AC:

103

AN:

1447634

Hom.:

Cov.:

AF XY:

0.0000654

AC XY:

AN XY:

719006

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33122

American (AMR)

AF:

0.00

AC:

AN:

43048

Ashkenazi Jewish (ASJ)

AF:

0.00240

AC:

AN:

25808

East Asian (EAS)

AF:

0.00

AC:

AN:

39022

South Asian (SAS)

AF:

0.00

AC:

AN:

84284

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.0000280

AC:

AN:

1105280

Other (OTH)

AF:

0.000151

AC:

AN:

59768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.0000855

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41408

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67972

Other (OTH)

AF:

0.00

AC:

AN:

2084

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:

0.000184

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000496

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 63

Pathogenic:2Uncertain:1

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as Uncertain Significance - Insufficient Evidence, for Epileptic encephalopathy, early infantile, 63, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Jun 25, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Nov 17, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

4p partial monosomy syndrome;C4693810:Developmental and epileptic encephalopathy, 63

Uncertain:1

Jan 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Uncertain:1

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 128 of the CPLX1 protein (p.Leu128Met). This variant is present in population databases (rs371709824, gnomAD 0.2%). This missense change has been observed in individual(s) with severe infantile myoclonic epilepsy and intellectual disability (PMID: 28422131). ClinVar contains an entry for this variant (Variation ID: 523650). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.051

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.2

M;.

PhyloP100

7.5

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.63

N;N

REVEL

Benign

0.15

Sift

Benign

0.12

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.95

P;P

Vest4

0.37

MVP

0.34

MPC

1.1

ClinPred

0.38

GERP RS

3.8

Varity_R

0.29

gMVP

0.58

Mutation Taster

=13/87

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over