rs1555794286

Positions:

• chr20-10293197-T-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 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 15 ACMG points.

• PM1: In a domain t-SNARE coiled-coil homology 1 (size 62) in uniprot entity SNP25_HUMAN there are 11 pathogenic changes around while only 2 benign (85%) in NM_130811.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SNAP25. . Gene score misZ 2.9553 (greater than the threshold 3.09). Trascript score misZ 3.1929 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	UniProt
SNAP25	NM_130811.4	c.200T>A	p.Ile67Asn	missense_variant	5/8	ENST00000254976.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNAP25	ENST00000254976.7	c.200T>A	p.Ile67Asn	missense_variant	5/8	1	NM_130811.4	P5
SNAP25-AS1	ENST00000421143.6	n.5+75518A>T		intron_variant, non_coding_transcript_variant		5

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2018

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

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jul 15, 2020

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

Congenital myasthenic syndrome 18 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 09, 2014

- -

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;.
MutationTaster	Benign	1.0	D;D
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;