rs184769423

chr2-165314101-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001040142.2(SCN2A):c.1376A>C(p.Glu459Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000973 in 1,613,302 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000074 (1 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 6.28

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SCN2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.071101755).
• BP6: Variant 2-165314101-A-C is Benign according to our data. Variant chr2-165314101-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130213.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000322 (49/152264) while in subpopulation AFR AF= 0.00101 (42/41552). AF 95% confidence interval is 0.000768. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.1376A>C	p.Glu459Ala	missense_variant	10/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.1376A>C	p.Glu459Ala	missense_variant	10/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.1376A>C	p.Glu459Ala	missense_variant	10/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.1376A>C	p.Glu459Ala	missense_variant	10/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000100 AC: 25 AN: 249676 Hom.: 1 AF XY: 0.000111 AC XY: 15 AN XY: 134954

Gnomad AFR exome AF: 0.000741

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000533

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000739 AC: 108 AN: 1461038 Hom.: 1 Cov.: 32 AF XY: 0.0000798 AC XY: 58 AN XY: 726816

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74450

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000279 Hom.: 0

Bravo AF: 0.000355

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2018	This variant is associated with the following publications: (PMID: 30564305) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 14, 2018	- -

Febrile seizure (within the age range of 3 months to 6 years) Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Neurology, Children’s Hospital of Chongqing Medical University

-

- -

Pyridoxine-dependent epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Apr 21, 2017

- -

Complex neurodevelopmental disorder Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Jan 29, 2019

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-01-29 and interpreted as Variant of Uncertain significance. Variant was initially reported on 2017-08-15 by GTR ID of laboratory name 25969. The reporting laboratory might also submit to ClinVar. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 12, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	23
Dann	Benign	0.95
Eigen	Benign	-0.083
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T;.;T;.;.;.;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.071	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.41	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.9	D;N;.;.;.;.;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.31	T;T;.;.;.;.;T;T
Sift4G	Benign	0.37	T;T;.;.;T;.;T;T
Polyphen		0.011, 0.018	.;B;B;.;B;B;B;B
Vest4		0.34, 0.34, 0.35
MVP		0.66
ClinPred		0.061	T
GERP RS		5.8
Varity_R		0.21
gMVP		0.84

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

Other links and lift over

dbSNP: rs184769423; hg19: chr2-166170611;