rs2116658

Variant names:

• chr2-165310162-C-T
• rs2116658
• NM_001040142.2:c.698-161C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001040142.2(SCN2A):​c.698-161C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 152,012 control chromosomes in the GnomAD database, including 6,911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). The gene SCN2A is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.29 (6911 hom., cov: 33)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.92
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• episodic ataxia, type 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 3

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for SCN2A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-165310162-C-T is Benign according to our data. Variant chr2-165310162-C-T is described in ClinVar as Benign. ClinVar VariationId is 669359.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040142.2. 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
	SCN2A	NM_001040142.2	MANE Select	c.698-161C>T		intron	N/A	NP_001035232.1	Q99250-1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.698-161C>T		intron	N/A	NP_001358175.1	Q99250-2
	SCN2A	NM_001040143.2		c.698-161C>T		intron	N/A	NP_001035233.1	Q99250-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN2A	ENST00000375437.7	TSL:5 MANE Select	c.698-161C>T		intron	N/A	ENSP00000364586.2	Q99250-1
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.698-161C>T		intron	N/A	ENSP00000486885.1	Q99250-2
	SCN2A	ENST00000283256.10	TSL:1	c.698-161C>T		intron	N/A	ENSP00000283256.6	Q99250-1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44761 AN: 151896 Hom.: 6907 Cov.: 33

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.332

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.295 AC: 44770 AN: 152012 Hom.: 6911 Cov.: 33 AF XY: 0.288 AC XY: 21370 AN XY: 74322

African (AFR) AF: 0.306 AC: 12697 AN: 41452

American (AMR) AF: 0.304 AC: 4637 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1588 AN: 3468

East Asian (EAS) AF: 0.146 AC: 756 AN: 5182

South Asian (SAS) AF: 0.294 AC: 1412 AN: 4806

European-Finnish (FIN) AF: 0.143 AC: 1518 AN: 10584

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21098 AN: 67942

Other (OTH) AF: 0.329 AC: 693 AN: 2108

Alfa AF: 0.307 Hom.: 3822

Bravo AF: 0.306

Asia WGS AF: 0.208 AC: 724 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.77
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs2116658; hg19: chr2-166166672;