rs997508

Variant names:

• chr2-165309946-C-T
• rs997508
• NM_001040142.2:c.698-377C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001040142.2(SCN2A):​c.698-377C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 151,942 control chromosomes in the GnomAD database, including 24,858 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.57 (24858 hom., cov: 33)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.943
• Publications: 2 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 Submitted by: ClinGen, Illumina
• developmental and epileptic encephalopathy, 11

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.698-377C>T		intron_variant	Intron 6 of 26	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.698-377C>T		intron_variant	Intron 6 of 26	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.698-377C>T		intron_variant	Intron 6 of 26	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.698-377C>T		intron_variant	Intron 6 of 26	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.698-377C>T		intron_variant	Intron 6 of 26	1		ENSP00000283256.6
SCN2A	ENST00000424833.5	c.698-377C>T		intron_variant	Intron 6 of 10	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85922 AN: 151826 Hom.: 24848 Cov.: 33

Gnomad AFR AF: 0.624

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.567

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

GnomAD4 genome AF: 0.566 AC: 85963 AN: 151942 Hom.: 24858 Cov.: 33 AF XY: 0.558 AC XY: 41410 AN XY: 74266

African (AFR) AF: 0.624 AC: 25846 AN: 41448

American (AMR) AF: 0.494 AC: 7527 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2196 AN: 3468

East Asian (EAS) AF: 0.294 AC: 1516 AN: 5162

South Asian (SAS) AF: 0.486 AC: 2344 AN: 4824

European-Finnish (FIN) AF: 0.471 AC: 4974 AN: 10550

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39808 AN: 67920

Other (OTH) AF: 0.561 AC: 1185 AN: 2112

Alfa AF: 0.569 Hom.: 3258

Bravo AF: 0.568

Asia WGS AF: 0.383 AC: 1336 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.44
DANN	Benign	0.53
PhyloP100		-0.94
Mutation Taster		=99/1	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: rs997508; hg19: chr2-166166456;