rs186154973

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The c.1571G>A variant in SCN2A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 524 (p.Arg524Gln). The highest population minor allele frequency in gnomAD v2.1.1 is 0.1504% (30/19942 alleles) in Asian population, which is higher than the ClinGen Epilepsy Sodium Channel VCEP threshold (0.01%) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.192, evidence that does not predict a damaging effect on SCN2A function (BP4). In summary, this variant meets the criteria to be classified as BENIGN for autosomal dominant complex neurodevelopmental disorder based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1 and BP4. (Version 1; approved 6/13/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1939839/MONDO:0100038/068

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

SCN2A
NM_001040142.2 missense

Scores

2
17

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.875
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
For more information check the summary or visit ClinGen Evidence Repository.
BA1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SCN2ANM_001040142.2 linkuse as main transcriptc.1571G>A p.Arg524Gln missense_variant 11/27 ENST00000375437.7 NP_001035232.1
SCN2ANM_001371246.1 linkuse as main transcriptc.1571G>A p.Arg524Gln missense_variant 11/27 ENST00000631182.3 NP_001358175.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCN2AENST00000375437.7 linkuse as main transcriptc.1571G>A p.Arg524Gln missense_variant 11/275 NM_001040142.2 ENSP00000364586 P1Q99250-1
SCN2AENST00000631182.3 linkuse as main transcriptc.1571G>A p.Arg524Gln missense_variant 11/275 NM_001371246.1 ENSP00000486885 Q99250-2

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152168
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00174
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000133
AC:
33
AN:
248802
Hom.:
0
AF XY:
0.0000965
AC XY:
13
AN XY:
134694
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00152
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000899
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000568
AC:
83
AN:
1461772
Hom.:
0
Cov.:
32
AF XY:
0.0000509
AC XY:
37
AN XY:
727172
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00156
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152286
Hom.:
0
Cov.:
33
AF XY:
0.0000806
AC XY:
6
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00174
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000718
ExAC
AF:
0.000115
AC:
14
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2021- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsSep 21, 2017- -
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 17, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.39
T;.;T;.;T;T;.
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.35
FATHMM_MKL
Benign
0.52
D
LIST_S2
Uncertain
0.89
D;.;D;.;.;.;D
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.016
T;T;T;T;T;T;T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
0.0
N;N;.;N;N;N;N
MutationTaster
Benign
0.97
N;N;N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
0.38
N;.;.;.;.;N;N
REVEL
Benign
0.19
Sift
Benign
0.39
T;.;.;.;.;T;T
Sift4G
Benign
0.50
T;.;.;T;.;T;T
Polyphen
0.0030
B;B;.;B;B;B;B
Vest4
0.35
MVP
0.73
ClinPred
0.031
T
GERP RS
2.7
Varity_R
0.056
gMVP
0.59

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: rs186154973; hg19: chr2-166172168; COSMIC: COSV51842513; COSMIC: COSV51842513; API