chr2-165309431-T-G

Variant names:

• chr2-165309431-T-G
• rs1553567561
• NM_001040142.2:c.685T>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001040142.2(SCN2A):​c.685T>G​(p.Ser229Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S229T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 chr2-165309431-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 834051.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 genetic developmental and epileptic encephalopathy, episodic ataxia, type 9, seizures, benign familial infantile, 3, complex neurodevelopmental disorder, benign familial neonatal-infantile seizures, Dravet syndrome, infantile spasms, developmental and epileptic encephalopathy, 11, intellectual disability, benign familial infantile epilepsy, malignant migrating partial seizures of infancy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 2-165309431-T-G is Pathogenic according to our data. Variant chr2-165309431-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 464920.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.685T>G	p.Ser229Ala	missense_variant	Exon 6 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.697+175T>G		intron_variant	Intron 6 of 26	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.685T>G	p.Ser229Ala	missense_variant	Exon 6 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000283256.10	c.685T>G	p.Ser229Ala	missense_variant	Exon 6 of 27	1		ENSP00000283256.6
SCN2A	ENST00000424833.5	c.685T>G	p.Ser229Ala	missense_variant	Exon 6 of 11	1		ENSP00000406454.2
SCN2A	ENST00000631182.3	c.697+175T>G		intron_variant	Intron 6 of 26	5	NM_001371246.1	ENSP00000486885.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Feb 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with alanine at codon 229 of the SCN2A protein (p.Ser229Ala). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and alanine. This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported to be de novo in an individual affected with seizures (Invitae database). ClinVar contains an entry for this variant (Variation ID: 464920). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;D;T;D;D;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.70	T;T;T;.;.;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;M;.;M;M;.
PhyloP100		8.0
PROVEAN	Uncertain	-2.6	D;D;.;.;D;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;.;.;D;.
Sift4G	Benign	0.16	T;T;.;.;T;T
Polyphen		0.99	.;D;.;D;D;.
Vest4		0.73, 0.73
MutPred		0.54		Gain of ubiquitination at K226 (P = 0.0693);Gain of ubiquitination at K226 (P = 0.0693);.;Gain of ubiquitination at K226 (P = 0.0693);Gain of ubiquitination at K226 (P = 0.0693);.;
MVP		0.93
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.68
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553567561; hg19: chr2-166165941;