rs13025009

Positions:

• chr2-165313563-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040142.2(SCN2A):​c.1035-57A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,602,620 control chromosomes in the GnomAD database, including 32,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2356 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30638 hom.)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.530

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

SCN2A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-165313563-A-G is Benign according to our data. Variant chr2-165313563-A-G is described in ClinVar as [Benign]. Clinvar id is 670843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165313563-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.1035-57A>G		intron_variant		ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.1035-57A>G		intron_variant		ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.1035-57A>G		intron_variant		5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.1035-57A>G		intron_variant		5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.1035-57A>G		intron_variant		1		ENSP00000283256.6
SCN2A	ENST00000424833.5	c.1035-57A>G		intron_variant		1		ENSP00000406454.2

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23778 AN: 151934 Hom.: 2358 Cov.: 32

Gnomad AFR AF: 0.0545

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.302

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.201 AC: 290843 AN: 1450566 Hom.: 30638 AF XY: 0.203 AC XY: 146593 AN XY: 722312

Gnomad4 AFR exome AF: 0.0518

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.302

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.0907

Gnomad4 NFE exome AF: 0.209

Gnomad4 OTH exome AF: 0.202

GnomAD4 genome AF: 0.156 AC: 23763 AN: 152054 Hom.: 2356 Cov.: 32 AF XY: 0.153 AC XY: 11380 AN XY: 74328

Gnomad4 AFR AF: 0.0543

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.302

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.0750

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.189

Alfa AF: 0.197 Hom.: 1379

Bravo AF: 0.159

Asia WGS AF: 0.174 AC: 608 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 32. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.48

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: rs13025009; hg19: chr2-166170073; COSMIC: COSV51832709; COSMIC: COSV51832709;