chr2-165373331-G-A

Position:

• chr2-165373331-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.3956G>A​(p.Arg1319Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1319L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 19 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S4 of repeat III (size 18) in uniprot entity SCN2A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001040142.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-165373331-G-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN2A. . Trascript score misZ 8.7114 (greater than threshold 3.09). GenCC has associacion of gene with seizures, benign familial infantile, 3, Dravet syndrome, benign familial neonatal-infantile seizures, malignant migrating partial seizures of infancy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 11, developmental and epileptic encephalopathy, West syndrome, benign familial infantile epilepsy, episodic ataxia, type 9.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 2-165373331-G-A is Pathogenic according to our data. Variant chr2-165373331-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165373331-G-A is described in UniProt as null. Variant chr2-165373331-G-A is described in UniProt as null. Variant chr2-165373331-G-A is described in UniProt as null. Variant chr2-165373331-G-A is described in UniProt as null. Variant chr2-165373331-G-A is described in UniProt as null. Variant chr2-165373331-G-A is described in UniProt as null. Variant chr2-165373331-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.3956G>A	p.Arg1319Gln	missense_variant	21/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.3956G>A	p.Arg1319Gln	missense_variant	21/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.3956G>A	p.Arg1319Gln	missense_variant	21/27	5	NM_001040142.2	ENSP00000364586	P1
SCN2A	ENST00000631182.3	c.3956G>A	p.Arg1319Gln	missense_variant	21/27	5	NM_001371246.1	ENSP00000486885

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461066 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Seizures, benign familial infantile, 3 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 07, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	May 24, 2017	- -
Likely pathogenic, no assertion criteria provided	research	Department of Neurology, Children’s Hospital of Chongqing Medical University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 05, 2021	_x000D_ Criteria applied: PS3, PM5_STR, PP1_STR, PS4_MOD, PM1, PM2_SUP, PP3 -

Complex neurodevelopmental disorder Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	provider interpretation	GenomeConnect - Simons Searchlight	Aug 02, 2016	Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-08-02 and interpreted as Pathogenic. Variant was initially reported on 2015-08-14 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -
not provided, no classification provided	literature only	Channelopathy-Associated Epilepsy Research Center	-	- -

Developmental and epileptic encephalopathy, 11 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2004

- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Neurology Department, Shenzhen Children's Hospital

Feb 16, 2022

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1319 of the SCN2A protein (p.Arg1319Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile-onset epileptic encephalopathy (PMID: 15048894, 28379373). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12880). 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 expected to disrupt SCN2A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN2A function (PMID: 18479388). This variant disrupts the p.Arg1319 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27781031). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Benign familial infantile epilepsy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Neurology Department, Shenzhen Children's Hospital

Feb 16, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2023

Reported in multiple unrelated families with benign familial neonatal-infantile seizures (BFNIS) and benign familial infantile seizures (BFIS) (PMID: 15048894, 23360469); Published functional studies demonstrates loss of Nav1.2 channel function and neuronal hyperexcitability (PMID: 18479388, 17021166); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Multiple pathogenic missense variants at this residue (p.R1319W, p.R1319L) have been reported in association with SCN2A-related disorders (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29307654, 28379373, 28488083, 29635106, 17021166, 23360469, 28717674, 29655203, 31558572, 32090326, 35431799, 18479388, 15048894) -

benign sporadic infantile epilepsy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;T;.;D;D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.6	D;.;.;.;.;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Benign	0.16	T;.;.;T;.;T;T
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.82
MutPred		0.83		Loss of methylation at R1319 (P = 0.0037);Loss of methylation at R1319 (P = 0.0037);.;Loss of methylation at R1319 (P = 0.0037);Loss of methylation at R1319 (P = 0.0037);Loss of methylation at R1319 (P = 0.0037);Loss of methylation at R1319 (P = 0.0037);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.83
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs121917753; hg19: chr2-166229841; COSMIC: COSV51836018;