NM_001040142.2:c.387-10G>A

Variant names:

• chr2-165307838-G-A
• rs2304015
• NM_001040142.2:c.387-10G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040142.2(SCN2A):​c.387-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00362 in 1,586,860 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (107 hom.)
• Consequence: SCN2A NM_001040142.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.27
• 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 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-165307838-G-A is Benign according to our data. Variant chr2-165307838-G-A is described in ClinVar as Benign. ClinVar VariationId is 130221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0674 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN2A	NM_001040142.2	MANE Select	c.387-10G>A		intron	N/A	NP_001035232.1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.387-10G>A		intron	N/A	NP_001358175.1
	SCN2A	NM_001040143.2		c.387-10G>A		intron	N/A	NP_001035233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN2A	ENST00000375437.7	TSL:5 MANE Select	c.387-10G>A		intron	N/A	ENSP00000364586.2
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.387-10G>A		intron	N/A	ENSP00000486885.1
	SCN2A	ENST00000283256.10	TSL:1	c.387-10G>A		intron	N/A	ENSP00000283256.6

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 581 AN: 152090 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.0738

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.00321

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00730 AC: 1834 AN: 251174 AF XY: 0.00696

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00745

Gnomad EAS exome AF: 0.0739

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00360 AC: 5170 AN: 1434654 Hom.: 107 Cov.: 27 AF XY: 0.00371 AC XY: 2655 AN XY: 715592

African (AFR) AF: 0.000183 AC: 6 AN: 32868

American (AMR) AF: 0.000246 AC: 11 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00782 AC: 203 AN: 25960

East Asian (EAS) AF: 0.0746 AC: 2944 AN: 39456

South Asian (SAS) AF: 0.00428 AC: 367 AN: 85656

European-Finnish (FIN) AF: 0.00272 AC: 145 AN: 53368

Middle Eastern (MID) AF: 0.00210 AC: 12 AN: 5714

European-Non Finnish (NFE) AF: 0.00113 AC: 1229 AN: 1087508

Other (OTH) AF: 0.00426 AC: 253 AN: 59438

GnomAD4 genome AF: 0.00380 AC: 578 AN: 152206 Hom.: 12 Cov.: 32 AF XY: 0.00460 AC XY: 342 AN XY: 74420

African (AFR) AF: 0.000241 AC: 10 AN: 41556

American (AMR) AF: 0.000589 AC: 9 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.0734 AC: 381 AN: 5188

South Asian (SAS) AF: 0.00644 AC: 31 AN: 4816

European-Finnish (FIN) AF: 0.00321 AC: 34 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 67972

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00168 Hom.: 1

Bravo AF: 0.00437

Asia WGS AF: 0.0350 AC: 120 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Seizures, benign familial infantile, 3 (1)
-	-	1	Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.18
DANN	Benign	0.74
PhyloP100		-1.3
PromoterAI		-0.0043	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2304015; hg19: chr2-166164348; COSMIC: COSV51848205; COSMIC: COSV51848205;