rs362562

Variant names:

• chr20-10262538-G-A
• rs362562
• NM_130811.4:c.-63-12891G>A

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_130811.4(SNAP25):c.-63-12891G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.362 (AC=54,961) in the gnomAD database across 151,862 control chromosomes, including 10,738 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.427. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10738 hom., cov: 32)
• Consequence: SNAP25 NM_130811.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.138
• Publications: 5 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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 18

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4269 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNAP25	NM_130811.4	MANE Select	c.-63-12891G>A		intron	N/A	NP_570824.1	P60880-1
	SNAP25	NM_001322902.2		c.-63-12891G>A		intron	N/A	NP_001309831.1	P60880-2
	SNAP25	NM_001322903.2		c.-63-12891G>A		intron	N/A	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.-63-12891G>A		intron	N/A	ENSP00000254976.3	P60880-1
	SNAP25	ENST00000304886.6	TSL:1	c.-63-12891G>A		intron	N/A	ENSP00000307341.2	P60880-2
	SNAP25	ENST00000961779.1		c.-63-12891G>A		intron	N/A	ENSP00000631838.1	A0ACI8V5C3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.362	AC:54938	Hom:10740	AN:151748	Cov:32
GnomAD4 genome	AF: 0.362	AC:54961	Hom:10738	AN:151862	Cov:32
TOPMed (Bravo)	AF: 0.359	AC:95068	Hom:18567	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.414	AC:114614	Hom:24178	AN:277014	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.423	AC:988	Hom:228	AN:2334	Cov:
ChinaMAP Phase 1	AF: 0.0961	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.447	AC:134	Hom:	AN:300	Cov:
Korea4K (4,157 Koreans)	AF: 0.118	AC:854	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.648	AC:114	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.138	AC:16883	Hom:1167	AN:122552	Cov:
Turkish Variome	AF: 0.457	AC:707	Hom:170	AN:1546	Cov:
UK10K	AF: 0.409	AC:3093	Hom:	AN:7562	Cov:

Showing 12 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.2
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.8
DANN	Benign	0.75
GPN-Star LLR	N/A	2.3
GPN-Star score	N/A	-1.9
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.14

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs362562;

hg19: chr20-10243186;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar