20-10275517-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PM2 PP2 BP4_Moderate BP6_Moderate

The NM_130811.4(SNAP25):c.26A>G(p.Asn9Ser) 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 benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N9H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SNAP25 NM_130811.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.58

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a helix (size 72) in uniprot entity SNP25_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_130811.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SNAP25
• BP4: Computational evidence support a benign effect (MetaRNN=0.16148716).
• BP6: Variant 20-10275517-A-G is Benign according to our data. Variant chr20-10275517-A-G is described in ClinVar as [Benign]. Clinvar id is 665210.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNAP25	NM_130811.4	c.26A>G	p.Asn9Ser	missense_variant	2/8	ENST00000254976.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNAP25	ENST00000254976.7	c.26A>G	p.Asn9Ser	missense_variant	2/8	1	NM_130811.4	P5
SNAP25-AS1	ENST00000421143.6	n.6-78580T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000414 AC: 1 AN: 241630 Hom.: 0 AF XY: 0.00000767 AC XY: 1 AN XY: 130312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000909

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	20
Dann	Benign	0.84
DEOGEN2	Benign	0.25	T;.;.
Eigen	Benign	-0.091
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.25	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.77
MutPred		0.16		Gain of phosphorylation at N9 (P = 0.0013);Gain of phosphorylation at N9 (P = 0.0013);Gain of phosphorylation at N9 (P = 0.0013);
MVP		0.20
MPC		0.087
ClinPred		0.22	T
GERP RS		6.1
Varity_R		0.46
gMVP		0.73

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: rs1364361088; hg19: chr20-10256165;