4-786566-C-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_006651.4(CPLX1):​c.340G>T​(p.Glu114*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CPLX1 NM_006651.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.16 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• 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>T	p.Glu114*	stop_gained	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>T	p.Glu114*	stop_gained	Exon 4 of 4	ENSP00000305613.6	O14810
	CPLX1	ENST00000892263.1		c.340G>T	p.Glu114*	stop_gained	Exon 4 of 4	ENSP00000562322.1
	CPLX1	ENST00000892264.1		c.340G>T	p.Glu114*	stop_gained	Exon 4 of 4	ENSP00000562323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457642 Hom.: 0 Cov.: 36 AF XY: 0.00000276 AC XY: 2 AN XY: 724838

African (AFR) AF: 0.0000599 AC: 2 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: 0.00 AC: 0 AN: 1110324

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.5
Vest4		0.80
GERP RS		3.8
Mutation Taster		=18/182	disease causing

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;