ENST00000480032.4:n.8_10dupTTT

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The ENST00000480032.4(SCN2A):n.8_10dupTTT variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00076 ( 1 hom., cov: 11)

Exomes 𝑓: 0.0053 ( 1 hom. )

Consequence

SCN2A
ENST00000480032.4 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

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 -10 ACMG points.

BP6

Variant 2-165294040-A-ATTT is Benign according to our data. Variant chr2-165294040-A-ATTT is described in ClinVar as [Benign]. Clinvar id is 2651482.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000762 (79/103682) while in subpopulation NFE AF = 0.0012 (63/52558). AF 95% confidence interval is 0.000961. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 11. This position passed quality control check.

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2 link	c.-51-1722_-51-1720dupTTT		intron_variant	Intron 1 of 26	ENST00000375437.7	NP_001035232.1	Q99250-1
SCN2A	NM_001371246.1 link	c.-51-1722_-51-1720dupTTT		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.-136_-134dupTTT	5_prime_UTR_variant	Exon 1 of 27	1		ENSP00000283256.6	Q99250-1
SCN2A	ENST00000375437.7 link	c.-51-1722_-51-1720dupTTT	intron_variant	Intron 1 of 26	5	NM_001040142.2	ENSP00000364586.2	Q99250-1
SCN2A	ENST00000631182.3 link	c.-51-1722_-51-1720dupTTT	intron_variant	Intron 1 of 26	5	NM_001371246.1	ENSP00000486885.1	Q99250-2
SCN2A	ENST00000424833.5 link	c.-51-1722_-51-1720dupTTT	intron_variant	Intron 1 of 10	1		ENSP00000406454.2	F6U291

Frequencies

GnomAD3 genomes

AF:

0.000762

AC:

AN:

103646

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000341

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000905

Gnomad SAS

AF:

0.000682

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00120

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00530

AC:

2784

AN:

525350

Hom.:

Cov.:

AF XY:

0.00530

AC XY:

1294

AN XY:

244284

show subpopulations

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

African (AFR)

AF:

0.00143

AC:

AN:

9786

American (AMR)

AF:

0.00457

AC:

AN:

656

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3072

East Asian (EAS)

AF:

0.00701

AC:

AN:

2426

South Asian (SAS)

AF:

0.00405

AC:

AN:

10372

European-Finnish (FIN)

AF:

0.00

AC:

AN:

182

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

908

European-Non Finnish (NFE)

AF:

0.00541

AC:

2602

AN:

480740

Other (OTH)

AF:

0.00552

AC:

AN:

17208

⚠️ 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: 0.304

Heterozygous variant carriers

212

424

637

849

1061

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000762

AC:

AN:

103682

Hom.:

Cov.:

AF XY:

0.000751

AC XY:

AN XY:

47926

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

27710

American (AMR)

AF:

0.000340

AC:

AN:

8824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2632

East Asian (EAS)

AF:

0.000906

AC:

AN:

3310

South Asian (SAS)

AF:

0.000683

AC:

AN:

2928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3462

Middle Eastern (MID)

AF:

0.00

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.00120

AC:

AN:

52558

Other (OTH)

AF:

0.00

AC:

AN:

1348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00128

Hom.:

203

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SCN2A: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.28

Mutation Taster

=300/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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ENST00000480032.4:n.8_10dupTTT

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