20-10275538-G-A

Position:

• chr20-10275538-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The ENST00000254976.7(SNAP25):​c.47G>A​(p.Arg16Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SNAP25 ENST00000254976.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

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 3 ACMG points.

• PM1: In a helix (size 72) in uniprot entity SNP25_HUMAN there are 12 pathogenic changes around while only 3 benign (80%) in ENST00000254976.7
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14385557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNAP25	NM_130811.4	c.47G>A	p.Arg16Gln	missense_variant	2/8	ENST00000254976.7	NP_570824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNAP25	ENST00000254976.7	c.47G>A	p.Arg16Gln	missense_variant	2/8	1	NM_130811.4	ENSP00000254976	P5
SNAP25-AS1	ENST00000421143.6	n.6-78601C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000417 AC: 1 AN: 239888 Hom.: 0 AF XY: 0.00000774 AC XY: 1 AN XY: 129266

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450808 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 18 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 856211). This variant has not been reported in the literature in individuals affected with SNAP25-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 16 of the SNAP25 protein (p.Arg16Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.30	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.33
MutPred		0.35		Loss of MoRF binding (P = 0.0974);Loss of MoRF binding (P = 0.0974);Loss of MoRF binding (P = 0.0974);
MVP		0.20
MPC		0.12
ClinPred		0.38	T
GERP RS		6.1
Varity_R		0.44
gMVP		0.65

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: rs760339630; hg19: chr20-10256186; COSMIC: COSV54773511;