rs140194137

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001040142.2(SCN2A):​c.3594G>A​(p.Arg1198Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000758 in 1,614,102 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0010 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00073 ( 5 hom. )

Consequence

SCN2A
NM_001040142.2 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0250
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
Variant 2-165367290-G-A is Benign according to our data. Variant chr2-165367290-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 139013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165367290-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.025 with no splicing effect.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00102 (155/152258) while in subpopulation SAS AF= 0.0027 (13/4820). AF 95% confidence interval is 0.00159. There are 4 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 155 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCN2ANM_001040142.2 linkc.3594G>A p.Arg1198Arg synonymous_variant Exon 19 of 27 ENST00000375437.7 NP_001035232.1 Q99250-1
SCN2ANM_001371246.1 linkc.3594G>A p.Arg1198Arg synonymous_variant Exon 19 of 27 ENST00000631182.3 NP_001358175.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCN2AENST00000375437.7 linkc.3594G>A p.Arg1198Arg synonymous_variant Exon 19 of 27 5 NM_001040142.2 ENSP00000364586.2 Q99250-1
SCN2AENST00000631182.3 linkc.3594G>A p.Arg1198Arg synonymous_variant Exon 19 of 27 5 NM_001371246.1 ENSP00000486885.1 Q99250-2
SCN2AENST00000283256.10 linkc.3594G>A p.Arg1198Arg synonymous_variant Exon 19 of 27 1 ENSP00000283256.6 Q99250-1

Frequencies

GnomAD3 genomes
AF:
0.00102
AC:
155
AN:
152140
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.0811
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00269
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.000779
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000835
AC:
210
AN:
251384
Hom.:
2
AF XY:
0.00107
AC XY:
146
AN XY:
135858
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000260
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00372
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000677
Gnomad OTH exome
AF:
0.00114
GnomAD4 exome
AF:
0.000731
AC:
1068
AN:
1461844
Hom.:
5
Cov.:
31
AF XY:
0.000811
AC XY:
590
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000268
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00352
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.000605
Gnomad4 OTH exome
AF:
0.000778
GnomAD4 genome
AF:
0.00102
AC:
155
AN:
152258
Hom.:
4
Cov.:
32
AF XY:
0.00124
AC XY:
92
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00270
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.000779
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000945
Hom.:
0
Bravo
AF:
0.00115
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.000873
EpiControl
AF:
0.000889

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Mar 06, 2014
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1
Aug 19, 2016
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Benign:1
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SCN2A: BP4, BP7 -

Seizures, benign familial infantile, 3 Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.55
CADD
Benign
4.6
DANN
Benign
0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs140194137; hg19: chr2-166223800; COSMIC: COSV51836238; API