rs121917754

Variant names:

• chr2-165354279-C-A
• rs121917754
• NM_001040142.2:c.3007C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001040142.2(SCN2A):c.3007C>A (p.Leu1003Ile) variant in SCN2A is a missense variant predicted to cause substitution of leucine by isoleucine at amino acid 1003 (p.Leu1003Ile). This variant has been reported in one family meeting phenotypic criteria for Complex Neurodevelopmental Disorder (MONDO:0100038 (PS4_Supporting; PMID 15048894). In this family, the variant was reported to segregate with Complex Neurodevelopmental Disorder (MONDO:0100038) in two meioses (father with two affected children). This does not meet the threshold of three meioses to apply PP1 (PMID 15048894). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Complex Neurodevelopmental Disorder (MONDO:0100038) based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM2_Supporting, PS4_Supporting. (ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 1.0.0; approved 10/22/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA122775/MONDO:0100038/068

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 1.93
• Publications: 8 publications found

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]

SCN2A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• episodic ataxia, type 9

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• seizures, benign familial infantile, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• benign familial infantile epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• benign familial neonatal-infantile seizures

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Dravet syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.3007C>A	p.Leu1003Ile	missense_variant	Exon 17 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.3007C>A	p.Leu1003Ile	missense_variant	Exon 17 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.3007C>A	p.Leu1003Ile	missense_variant	Exon 17 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.3007C>A	p.Leu1003Ile	missense_variant	Exon 17 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.3007C>A	p.Leu1003Ile	missense_variant	Exon 17 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Seizures, benign familial infantile, 3 Pathogenic:1

Apr 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Jun 20, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with isoleucine at codon 1003 of the SCN2A protein (p.Leu1003Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed to segregate with benign familial neonatal-infantile seizures in a family (PMID: 15048894). ClinVar contains an entry for this variant (Variation ID: 12881). This variant is not present in population databases (ExAC no frequency). -

Complex neurodevelopmental disorder Uncertain:1

Oct 22, 2024

ClinGen Epilepsy Sodium Channel Variant Curation Expert Panel, Clingen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001040142.2(SCN2A):c.3007C>A (p.Leu1003Ile) variant in SCN2A is a missense variant predicted to cause substitution of leucine by isoleucine at amino acid 1003 (p.Leu1003Ile). This variant has been reported in one family meeting phenotypic criteria for Complex Neurodevelopmental Disorder (MONDO:0100038 (PS4_Supporting; PMID 15048894). In this family, the variant was reported to segregate with Complex Neurodevelopmental Disorder (MONDO:0100038) in two meioses (father with two affected children). This does not meet the threshold of three meioses to apply PP1 (PMID 15048894). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Complex Neurodevelopmental Disorder (MONDO:0100038) based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: PM2_Supporting, PS4_Supporting. (ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 1.0.0; approved 10/22/2024). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;T;.;D;D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;.;D;.;.;.;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.7	M;M;.;M;M;M;M
PhyloP100		1.9
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.8	N;.;.;.;.;N;N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Benign	0.25	T;.;.;T;.;T;T
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.22
MutPred		0.90		Gain of MoRF binding (P = 0.1327);Gain of MoRF binding (P = 0.1327);.;Gain of MoRF binding (P = 0.1327);Gain of MoRF binding (P = 0.1327);Gain of MoRF binding (P = 0.1327);Gain of MoRF binding (P = 0.1327);
MVP		0.98
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.60
gMVP		0.84
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs121917754; hg19: chr2-166210789; COSMIC: COSV51835958;