rs362998

chr20-10296973-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_130811.4(SNAP25):c.330C>T(p.Asp110=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0818 in 1,613,744 control chromosomes in the GnomAD database, including 7,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1153 hom., cov: 33)
  • Exomes 𝑓: 0.079 (5974 hom.)
• Consequence: SNAP25 NM_130811.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.528

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 20-10296973-C-T is Benign according to our data. Variant chr20-10296973-C-T is described in ClinVar as [Benign]. Clinvar id is 587804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.528 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNAP25	NM_130811.4	c.330C>T	p.Asp110=	synonymous_variant	6/8	ENST00000254976.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNAP25	ENST00000254976.7	c.330C>T	p.Asp110=	synonymous_variant	6/8	1	NM_130811.4	P5
SNAP25-AS1	ENST00000421143.6	n.5+71742G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16630 AN: 152064 Hom.: 1152 Cov.: 33

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0646

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.108 AC: 26980 AN: 250880 Hom.: 1818 AF XY: 0.104 AC XY: 14094 AN XY: 135600

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.164

Gnomad ASJ exome AF: 0.0345

Gnomad EAS exome AF: 0.177

Gnomad SAS exome AF: 0.128

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.0667

Gnomad OTH exome AF: 0.0906

GnomAD4 exome AF: 0.0789 AC: 115363 AN: 1461564 Hom.: 5974 Cov.: 31 AF XY: 0.0799 AC XY: 58057 AN XY: 727076

Gnomad4 AFR exome AF: 0.182

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.0348

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.131

Gnomad4 NFE exome AF: 0.0620

Gnomad4 OTH exome AF: 0.0812

GnomAD4 genome AF: 0.110 AC: 16670 AN: 152180 Hom.: 1153 Cov.: 33 AF XY: 0.111 AC XY: 8262 AN XY: 74402

Gnomad4 AFR AF: 0.176

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0360

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.128

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.0646

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0741 Hom.: 665

Bravo AF: 0.113

Asia WGS AF: 0.159 AC: 553 AN: 3478

EpiCase AF: 0.0595

EpiControl AF: 0.0579

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2021

- -

Congenital myasthenic syndrome 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	3.5
Dann	Benign	0.89

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: rs362998; hg19: chr20-10277621; COSMIC: COSV54775530; COSMIC: COSV54775530;