4-786591-G-T

Variant names:

• chr4-786591-G-T
• rs1553851860
• NM_006651.4:c.315C>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_006651.4(CPLX1):​c.315C>A​(p.Cys105*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CPLX1 NM_006651.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -1.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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 0.222 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-786591-G-T is Pathogenic according to our data. Variant chr4-786591-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-786591-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLX1	NM_006651.4	c.315C>A	p.Cys105*	stop_gained	Exon 4 of 4	ENST00000304062.11	NP_006642.1
CPLX1	XM_011513391.2	c.270C>A	p.Cys90*	stop_gained	Exon 3 of 3		XP_011511693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPLX1	ENST00000304062.11	c.315C>A	p.Cys105*	stop_gained	Exon 4 of 4	1	NM_006651.4	ENSP00000305613.6
CPLX1	ENST00000505203.1	c.252C>A	p.Cys84*	stop_gained	Exon 5 of 5	2		ENSP00000425960.1
CPLX1	ENST00000504062.1	c.270C>A	p.Cys90*	stop_gained	Exon 3 of 3	3		ENSP00000421947.1
CPLX1	ENST00000506404.1	n.368C>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 63 Pathogenic:3

Jun 25, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance: 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

- -

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely Pathogenic, 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. PVS1-Strong => PVS1 downgraded in strength to Strong (https://www.ncbi.nlm.nih.gov/pubmed/28422131). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
DANN	Benign	0.97
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.29	N
Vest4		0.80
GERP RS		-3.6

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

LitVar

Other links and lift over

dbSNP: rs1553851860; hg19: chr4-780379;