NM_001040142.2:c.-51-1983G>C

Variant names:

• chr2-165293790-G-C
• rs12614399
• NM_001040142.2:c.-51-1983G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001040142.2(SCN2A):​c.-51-1983G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 968,570 control chromosomes in the GnomAD database, including 29,213 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 0.23 (4469 hom., cov: 30)
  • Exomes 𝑓: 0.24 (24744 hom.)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.95
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-165293790-G-C is Benign according to our data. Variant chr2-165293790-G-C is described in ClinVar as Benign. ClinVar VariationId is 1245138.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 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.-51-1983G>C		intron	N/A	NP_001035232.1	Q99250-1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.-51-1983G>C		intron	N/A	NP_001358175.1	Q99250-2
	SCN2A	NM_001040143.2		c.-51-1983G>C		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.-51-1983G>C		intron	N/A	ENSP00000364586.2	Q99250-1
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.-51-1983G>C		intron	N/A	ENSP00000486885.1	Q99250-2
	SCN2A	ENST00000424833.5	TSL:1	c.-51-1983G>C		intron	N/A	ENSP00000406454.2	F6U291

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35557 AN: 151460 Hom.: 4457 Cov.: 30

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.232

GnomAD4 exome AF: 0.244 AC: 199637 AN: 816994 Hom.: 24744 Cov.: 14 AF XY: 0.244 AC XY: 92327 AN XY: 377940

African (AFR) AF: 0.139 AC: 2153 AN: 15450

American (AMR) AF: 0.314 AC: 301 AN: 960

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 680 AN: 5052

East Asian (EAS) AF: 0.352 AC: 1249 AN: 3550

South Asian (SAS) AF: 0.245 AC: 3951 AN: 16156

European-Finnish (FIN) AF: 0.318 AC: 87 AN: 274

Middle Eastern (MID) AF: 0.138 AC: 219 AN: 1586

European-Non Finnish (NFE) AF: 0.247 AC: 184820 AN: 747190

Other (OTH) AF: 0.231 AC: 6177 AN: 26776

GnomAD4 genome AF: 0.235 AC: 35593 AN: 151576 Hom.: 4469 Cov.: 30 AF XY: 0.238 AC XY: 17610 AN XY: 74028

African (AFR) AF: 0.157 AC: 6491 AN: 41394

American (AMR) AF: 0.318 AC: 4843 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 474 AN: 3472

East Asian (EAS) AF: 0.365 AC: 1862 AN: 5104

South Asian (SAS) AF: 0.236 AC: 1132 AN: 4798

European-Finnish (FIN) AF: 0.284 AC: 2972 AN: 10454

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.250 AC: 16984 AN: 67816

Other (OTH) AF: 0.239 AC: 504 AN: 2110

Alfa AF: 0.246 Hom.: 608

Bravo AF: 0.236

Asia WGS AF: 0.306 AC: 1062 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	-0.86
CADD	Benign	0.17
DANN	Benign	0.37
PhyloP100		-2.9
PromoterAI		0.025	Neutral
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: rs12614399; hg19: chr2-166150300;