Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000283256.10(SCN2A):c.1785T>C(p.Asp595Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,614,178 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 7 hom., cov: 32)

Exomes 𝑓: 0.013 ( 146 hom. )

Consequence

SCN2A
ENST00000283256.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.633

Publications

9 publications found

Variant links:

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

SCN2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 2-165323269-T-C is Benign according to our data. Variant chr2-165323269-T-C is described in ClinVar as Benign. ClinVar VariationId is 130217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.633 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00999 (1522/152284) while in subpopulation AMR AF = 0.0176 (270/15300). AF 95% confidence interval is 0.0159. There are 7 homozygotes in GnomAd4. There are 733 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1522 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000283256.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN2A	NM_001040142.2	MANE Select	c.1785T>C	p.Asp595Asp	synonymous	Exon 12 of 27	NP_001035232.1
SCN2A	NM_001371246.1	MANE Plus Clinical	c.1785T>C	p.Asp595Asp	synonymous	Exon 12 of 27	NP_001358175.1
SCN2A	NM_001040143.2		c.1785T>C	p.Asp595Asp	synonymous	Exon 13 of 28	NP_001035233.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCN2A	ENST00000375437.7	TSL:5 MANE Select	c.1785T>C	p.Asp595Asp	synonymous	Exon 12 of 27	ENSP00000364586.2
SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.1785T>C	p.Asp595Asp	synonymous	Exon 12 of 27	ENSP00000486885.1
SCN2A	ENST00000283256.10	TSL:1	c.1785T>C	p.Asp595Asp	synonymous	Exon 12 of 27	ENSP00000283256.6

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1524

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00309

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.00950

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00414

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0142

Gnomad OTH

AF:

0.0125

GnomAD2 exomes

AF:

0.00952

AC:

2392

AN:

251292

AF XY:

0.00970

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.0115

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00490

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.0130

AC:

19046

AN:

1461894

Hom.:

146

Cov.:

AF XY:

0.0126

AC XY:

9189

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33480

American (AMR)

AF:

0.0119

AC:

530

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00819

AC:

214

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00225

AC:

194

AN:

86258

European-Finnish (FIN)

AF:

0.00569

AC:

304

AN:

53420

Middle Eastern (MID)

AF:

0.00745

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0153

AC:

17027

AN:

1112012

Other (OTH)

AF:

0.0109

AC:

661

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1206

2412

3617

4823

6029

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

646

1292

1938

2584

3230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00999

AC:

1522

AN:

152284

Hom.:

Cov.:

AF XY:

0.00984

AC XY:

733

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00308

AC:

128

AN:

41554

American (AMR)

AF:

0.0176

AC:

270

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00950

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00414

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0142

AC:

968

AN:

68022

Other (OTH)

AF:

0.0123

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

169

254

338

423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00976

Hom.:

Bravo

AF:

0.0106

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0168

EpiControl

AF:

0.0155

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Inborn genetic diseases (1)

Seizures, benign familial infantile, 3 (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

-0.53

CADD

Benign

2.5

(source)

DANN

Benign

0.52

PhyloP100

0.63

Mutation Taster

=73/27

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over