4-786566-C-T

Variant names:

• chr4-786566-C-T
• rs200267276
• NM_006651.4:c.340G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006651.4(CPLX1):​c.340G>A​(p.Glu114Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,609,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E114D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CPLX1 NM_006651.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

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>A	p.Glu114Lys	missense	Exon 4 of 4	NP_006642.1	O14810

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLX1	ENST00000304062.11	TSL:1 MANE Select	c.340G>A	p.Glu114Lys	missense	Exon 4 of 4	ENSP00000305613.6	O14810
	CPLX1	ENST00000892263.1		c.340G>A	p.Glu114Lys	missense	Exon 4 of 4	ENSP00000562322.1
	CPLX1	ENST00000892264.1		c.340G>A	p.Glu114Lys	missense	Exon 4 of 4	ENSP00000562323.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457642 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 724838

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 85470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110324

Other (OTH) AF: 0.00 AC: 0 AN: 60180

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74248

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.27
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.72		Gain of ubiquitination at E114 (P = 0.0054)
MVP		0.53
MPC		0.98
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.25
gMVP		0.59
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs200267276; hg19: chr4-780354; COSMIC: COSV99072887; COSMIC: COSV99072887;