20-10275513-C-A

Variant names:

• chr20-10275513-C-A
• rs555461700
• NM_130811.4:c.22C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_130811.4(SNAP25):​c.22C>A​(p.Arg8Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SNAP25 NM_130811.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130811.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNAP25	NM_130811.4	MANE Select	c.22C>A	p.Arg8Ser	missense	Exon 2 of 8	NP_570824.1	P60880-1
	SNAP25	NM_001322902.2		c.22C>A	p.Arg8Ser	missense	Exon 2 of 8	NP_001309831.1	P60880-2
	SNAP25	NM_001322903.2		c.22C>A	p.Arg8Ser	missense	Exon 3 of 9	NP_001309832.1	P60880-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNAP25	ENST00000254976.7	TSL:1 MANE Select	c.22C>A	p.Arg8Ser	missense	Exon 2 of 8	ENSP00000254976.3	P60880-1
	SNAP25	ENST00000304886.6	TSL:1	c.22C>A	p.Arg8Ser	missense	Exon 2 of 8	ENSP00000307341.2	P60880-2
	SNAP25	ENST00000961779.1		c.22C>A	p.Arg8Ser	missense	Exon 2 of 9	ENSP00000631838.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453582 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722290

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 43884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39492

South Asian (SAS) AF: 0.00 AC: 0 AN: 84210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107870

Other (OTH) AF: 0.00 AC: 0 AN: 60082

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0087	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.22
Sift	Benign	0.17	T
Sift4G	Benign	0.50	T
Polyphen		0.91	P
Vest4		0.79
MutPred		0.20		Gain of phosphorylation at R8 (P = 0.0056)
MVP		0.45
MPC		0.28
ClinPred		0.95	D
GERP RS		6.1
Varity_R		0.86
gMVP		0.94
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs555461700; hg19: chr20-10256161;