rs1555794286

Variant names:

• chr20-10293197-T-A
• rs1555794286
• NM_130811.4:c.200T>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_130811.4(SNAP25):​c.200T>A​(p.Ile67Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNAP25 NM_130811.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.02

Genes affected

SNAP25 (HGNC:11132): (synaptosome associated protein 25) Synaptic vesicle membrane docking and fusion is mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) located on the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices, one of which is supplied by v-SNARE and the other three by t-SNARE. For t-SNAREs on the plasma membrane, the protein syntaxin supplies one helix and the protein encoded by this gene contributes the other two. Therefore, this gene product is a presynaptic plasma membrane protein involved in the regulation of neurotransmitter release. Two alternative transcript variants encoding different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

SNAP25-AS1 (HGNC:44312): (SNAP25 antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SNAP25 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 2.9553 (below the threshold of 3.09). Trascript score misZ: 3.1929 (above the threshold of 3.09). GenCC associations: The gene is linked to presynaptic congenital myasthenic syndrome, congenital myasthenic syndrome 18, developmental and epileptic encephalopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861
• PP5: Variant 20-10293197-T-A is Pathogenic according to our data. Variant chr20-10293197-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 253030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10293197-T-A is described in UniProt as null. Variant chr20-10293197-T-A is described in UniProt as null. Variant chr20-10293197-T-A is described in UniProt as null. Variant chr20-10293197-T-A is described in UniProt as null. Variant chr20-10293197-T-A is described in UniProt as null. Variant chr20-10293197-T-A is described in UniProt as null. Variant chr20-10293197-T-A is described in UniProt as null. Variant chr20-10293197-T-A is described in UniProt as null. Variant chr20-10293197-T-A is described in UniProt as null. Variant chr20-10293197-T-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNAP25	NM_130811.4	c.200T>A	p.Ile67Asn	missense_variant	Exon 5 of 8	ENST00000254976.7	NP_570824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNAP25	ENST00000254976.7	c.200T>A	p.Ile67Asn	missense_variant	Exon 5 of 8	1	NM_130811.4	ENSP00000254976.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Sep 21, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

formerly reported from HGMD as NM_130811 c.200T>A -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Jul 15, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

Congenital myasthenic syndrome 18 Pathogenic:1

Dec 09, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.0	M;.
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.98
MutPred		0.51		Gain of ubiquitination at K72 (P = 0.0453);Gain of ubiquitination at K72 (P = 0.0453);
MVP		0.54
MPC		2.9
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.88
gMVP		1.0

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: rs1555794286; hg19: chr20-10273845;