chr2-165294040-A-AT

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000283256.10(SCN2A):c.-134dupT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.026 ( 98 hom., cov: 11)

Exomes 𝑓: 0.048 ( 38 hom. )

Consequence

SCN2A
ENST00000283256.10 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.275

Publications

0 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 -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.095 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2 link	c.-51-1720dupT		intron_variant	Intron 1 of 26	ENST00000375437.7	NP_001035232.1	Q99250-1
SCN2A	NM_001371246.1 link	c.-51-1720dupT		intron_variant	Intron 1 of 26	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SCN2A	ENST00000283256.10 link	c.-134dupT	5_prime_UTR_variant	Exon 1 of 27	1		ENSP00000283256.6	Q99250-1
SCN2A	ENST00000375437.7 link	c.-51-1720dupT	intron_variant	Intron 1 of 26	5	NM_001040142.2	ENSP00000364586.2	Q99250-1
SCN2A	ENST00000631182.3 link	c.-51-1720dupT	intron_variant	Intron 1 of 26	5	NM_001371246.1	ENSP00000486885.1	Q99250-2
SCN2A	ENST00000424833.5 link	c.-51-1720dupT	intron_variant	Intron 1 of 10	1		ENSP00000406454.2	F6U291

Frequencies

GnomAD3 genomes

AF:

0.0260

AC:

2696

AN:

103626

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0663

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.0171

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.0358

Gnomad FIN

AF:

0.00693

Gnomad MID

AF:

0.00526

Gnomad NFE

AF:

0.00302

Gnomad OTH

AF:

0.0208

GnomAD4 exome

AF:

0.0482

AC:

24503

AN:

508322

Hom.:

Cov.:

AF XY:

0.0482

AC XY:

11376

AN XY:

236238

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.113

AC:

1067

AN:

9420

American (AMR)

AF:

0.0796

AC:

AN:

628

Ashkenazi Jewish (ASJ)

AF:

0.0534

AC:

157

AN:

2942

East Asian (EAS)

AF:

0.147

AC:

348

AN:

2372

South Asian (SAS)

AF:

0.0908

AC:

913

AN:

10050

European-Finnish (FIN)

AF:

0.0465

AC:

AN:

172

Middle Eastern (MID)

AF:

0.0497

AC:

AN:

886

European-Non Finnish (NFE)

AF:

0.0450

AC:

20957

AN:

465216

Other (OTH)

AF:

0.0576

AC:

959

AN:

16636

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.315

Heterozygous variant carriers

1861

3722

5582

7443

9304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0260

AC:

2695

AN:

103662

Hom.:

Cov.:

AF XY:

0.0282

AC XY:

1352

AN XY:

47910

show subpopulations

African (AFR)

AF:

0.0662

AC:

1834

AN:

27698

American (AMR)

AF:

0.0177

AC:

156

AN:

8824

Ashkenazi Jewish (ASJ)

AF:

0.0171

AC:

AN:

2634

East Asian (EAS)

AF:

0.104

AC:

344

AN:

3306

South Asian (SAS)

AF:

0.0355

AC:

104

AN:

2926

European-Finnish (FIN)

AF:

0.00693

AC:

AN:

3462

Middle Eastern (MID)

AF:

0.00562

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.00303

AC:

159

AN:

52554

Other (OTH)

AF:

0.0208

AC:

AN:

1348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

112

224

337

449

561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

203

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Early Infantile Epileptic Encephalopathy, Autosomal Dominant

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Seizures, benign familial infantile, 3

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.28

Mutation Taster

=100/0

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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chr2-165294040-A-AT

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