rs201718767

chr2-165389559-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP2 BP4 BS1_Supporting BS2

The NM_001040142.2(SCN2A):c.5753G>A(p.Arg1918His) variant causes a missense change. The variant allele was found at a frequency of 0.0000706 in 1,613,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1918C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 3.93

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 229) in uniprot entity SCN2A_HUMAN there are 29 pathogenic changes around while only 7 benign (81%) in NM_001040142.2
• PP2: Missense variant where missense usually causes diseases, SCN2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.32569957).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000145 (22/152024) while in subpopulation NFE AF= 0.000279 (19/68022). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.5753G>A	p.Arg1918His	missense_variant	27/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.5753G>A	p.Arg1918His	missense_variant	27/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.5753G>A	p.Arg1918His	missense_variant	27/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.5753G>A	p.Arg1918His	missense_variant	27/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000878 AC: 22 AN: 250580 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135414

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000629 AC: 92 AN: 1461714 Hom.: 0 Cov.: 33 AF XY: 0.0000605 AC XY: 44 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000657

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74248

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2019	This variant is associated with the following publications: (PMID: 30564305, 27262167, 22029951, 11738931) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 24, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 28087622) Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -

Developmental and epileptic encephalopathy, 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 13, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2016

The p.R1918H variant (also known as c.5753G>A), located in coding exon 26 of the SCN2A gene, results from a G to A substitution at nucleotide position 5753. The arginine at codon 1918 is replaced by histidine, an amino acid with highly similar properties. This alteration was detected in one individual with febrile and tonic-clonic seizures; however, it was absent in the individual's niece who had pyknoleptic daily clusters of absence seizures. Of note, the alteration was not detected in three additional unaffected family members or in 92 controls (Haug K et al. Epilepsy Res., 2001 Dec;47:243-6). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1918 of the SCN2A protein (p.Arg1918His). This variant is present in population databases (rs201718767, gnomAD 0.02%). This missense change has been observed in individual(s) with childhood absence epilepsy and developmental and epileptic encephalopathy and/or epilepsy of infancy with migrating focal seizures (PMID: 11738931, 33000761, 35715422). ClinVar contains an entry for this variant (Variation ID: 590198). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCN2A protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SCN2A function (PMID: 28087622). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11;C5394520:Episodic ataxia, type 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

SCN2A NM_001040142.1 exon 27 p.Arg1918His (c.5753G>A): This variant has been reported in the literature in 1 individual with idiopathic generalized epilepsy, but did not segregate with disease in 1 affected family member (Haug 2001 PMID:11738931). This variant is present in 19/125972 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs201718767). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.0098	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;T;.;D;D;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.;D;.;.;.;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.2	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N;.;.;.;.;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.097	T;.;.;.;.;T;T
Sift4G	Benign	0.061	T;.;.;T;.;T;T
Polyphen		0.75	P;B;.;B;P;P;B
Vest4		0.089
MVP		0.87
ClinPred		0.099	T
GERP RS		5.9
Varity_R		0.42
gMVP		0.80

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: rs201718767; hg19: chr2-166246069; COSMIC: COSV51838555;