rs2304016

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001040142.2(SCN2A):c.971-32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00512 in 1,537,156 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0058 ( 20 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 169 hom. )

Consequence

SCN2A
NM_001040142.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.63

Publications

30 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 -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 2-165311993-A-G is Benign according to our data. Variant chr2-165311993-A-G is described in ClinVar as Benign. ClinVar VariationId is 1257386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2 link	c.971-32A>G		intron_variant	Intron 7 of 26	ENST00000375437.7	NP_001035232.1	Q99250-1
SCN2A	NM_001371246.1 link	c.971-32A>G		intron_variant	Intron 7 of 26	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN2A	ENST00000375437.7 link	c.971-32A>G	intron_variant	Intron 7 of 26	5	NM_001040142.2	ENSP00000364586.2	Q99250-1
SCN2A	ENST00000631182.3 link	c.971-32A>G	intron_variant	Intron 7 of 26	5	NM_001371246.1	ENSP00000486885.1	Q99250-2
SCN2A	ENST00000283256.10 link	c.971-32A>G	intron_variant	Intron 7 of 26	1		ENSP00000283256.6	Q99250-1
SCN2A	ENST00000424833.5 link	c.971-32A>G	intron_variant	Intron 7 of 10	1		ENSP00000406454.2	F6U291

Frequencies

GnomAD3 genomes

AF:

0.00584

AC:

888

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00891

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.0898

Gnomad SAS

AF:

0.00704

Gnomad FIN

AF:

0.00922

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00528

GnomAD2 exomes

AF:

0.0119

AC:

2907

AN:

244650

AF XY:

0.0108

show subpopulations

Gnomad AFR exome

AF:

0.000376

Gnomad AMR exome

AF:

0.0184

Gnomad ASJ exome

AF:

0.00925

Gnomad EAS exome

AF:

0.0897

Gnomad FIN exome

AF:

0.00816

Gnomad NFE exome

AF:

0.00200

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00505

AC:

6990

AN:

1384906

Hom.:

169

Cov.:

AF XY:

0.00505

AC XY:

3501

AN XY:

693192

show subpopulations

African (AFR)

AF:

0.000219

AC:

AN:

31950

American (AMR)

AF:

0.0180

AC:

797

AN:

44248

Ashkenazi Jewish (ASJ)

AF:

0.00959

AC:

245

AN:

25560

East Asian (EAS)

AF:

0.0884

AC:

3470

AN:

39236

South Asian (SAS)

AF:

0.00441

AC:

372

AN:

84330

European-Finnish (FIN)

AF:

0.00744

AC:

385

AN:

51778

Middle Eastern (MID)

AF:

0.00233

AC:

AN:

5584

European-Non Finnish (NFE)

AF:

0.00131

AC:

1371

AN:

1044592

Other (OTH)

AF:

0.00573

AC:

330

AN:

57628

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

374

748

1121

1495

1869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<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:

0.00581

AC:

884

AN:

152250

Hom.:

Cov.:

AF XY:

0.00705

AC XY:

525

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41550

American (AMR)

AF:

0.00890

AC:

136

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3468

East Asian (EAS)

AF:

0.0893

AC:

463

AN:

5182

South Asian (SAS)

AF:

0.00684

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00922

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00134

AC:

AN:

68006

Other (OTH)

AF:

0.00522

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

143

190

238

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:

0.00340

Hom.:

Bravo

AF:

0.00651

Asia WGS

AF:

0.0430

AC:

149

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

1.6

La Branchor

0.80

BranchPoint Hunter

4.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over