rs1553463676

Variant names:

• chr2-165389291-C-T
• rs1553463676
• NM_001040142.2:c.5485C>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PP2 PP3_Moderate PP5

The NM_001040142.2(SCN2A):​c.5485C>T​(p.Leu1829Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 4.86

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 10 ACMG points.

• PS1: Transcript NM_001040142.2 (SCN2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a topological_domain Cytoplasmic (size 229) in uniprot entity SCN2A_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_001040142.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 362 curated pathogenic missense variants (we use a threshold of 10). The gene has 36 curated benign missense variants. Trascript score misZ: 8.7114 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.857
• PP5: Variant 2-165389291-C-T is Pathogenic according to our data. Variant chr2-165389291-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 523396.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.5485C>T	p.Leu1829Phe	missense_variant	Exon 27 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.5485C>T	p.Leu1829Phe	missense_variant	Exon 27 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.5485C>T	p.Leu1829Phe	missense_variant	Exon 27 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.5485C>T	p.Leu1829Phe	missense_variant	Exon 27 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.5485C>T	p.Leu1829Phe	missense_variant	Exon 27 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

SCN2A-related disorder Pathogenic:1

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as de novo change in a patient with early infantile epileptic encephalopathy (PMID: 26993267, 32090326). The c.5485C>T (p.Leu1829Phe) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.5485C>T (p.Leu1829Phe) variant is classified as Likely Pathogenic. -

Developmental and epileptic encephalopathy, 11 Uncertain:1

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.5485C>T (p.Leu1829Phe) variant in SCN2A gene has been reported in heterozygous state in patients affected with Developmental and epileptic encephalopathy (Trump N et al. 2016). The p.Leu1829Phe variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid change p.Leu1829Phe in SCN2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 1829 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). -

Seizure Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;T;.;D;D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M;.;M;M;M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	D;.;.;.;.;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Uncertain	0.021	D;.;.;D;.;D;D
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.82
MutPred		0.41		Gain of methylation at K1833 (P = 0.0696);Gain of methylation at K1833 (P = 0.0696);.;Gain of methylation at K1833 (P = 0.0696);Gain of methylation at K1833 (P = 0.0696);Gain of methylation at K1833 (P = 0.0696);Gain of methylation at K1833 (P = 0.0696);
MVP		0.96
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.83
gMVP		0.99

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: rs1553463676; hg19: chr2-166245801;