NM_001040142.2:c.751G>A

Variant names:

• chr2-165310376-G-A
• rs1057519528
• NM_001040142.2:c.751G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.751G>A​(p.Val251Ile) 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. V251A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 10.0
• Publications: 3 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 17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr2-165310377-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1342691.Status of the report is no_assertion_criteria_provided, 0 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, 0.85
• PP5: Variant 2-165310376-G-A is Pathogenic according to our data. Variant chr2-165310376-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.751G>A	p.Val251Ile	missense_variant	Exon 7 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.751G>A	p.Val251Ile	missense_variant	Exon 7 of 27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.751G>A	p.Val251Ile	missense_variant	Exon 7 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.751G>A	p.Val251Ile	missense_variant	Exon 7 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.751G>A	p.Val251Ile	missense_variant	Exon 7 of 27	1		ENSP00000283256.6
SCN2A	ENST00000424833.5	c.751G>A	p.Val251Ile	missense_variant	Exon 7 of 11	1		ENSP00000406454.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 11 Pathogenic:3

Oct 23, 2023

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This heterozygous mis-sense variant is identified in a 5 year female with neonatal onset seizure from day 3 of life, followed by language delay, recurrent seizure, normal brain MRI, and abnormal EEG. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [REVEL=0.72] predicts deleterious nature of this variant [PP3]. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 375510] with “Pathogenic/Likely Pathogenic” interpretation by multiple submitter [PP5]. A different amino acid change, Val251Ala is a known pathogenic variant [PMID:29215089] [PM5]. This is a Mis-sense variant in a gene with low rate of benign miss-ense mutations and for which mis-sense mutation is a common mechanism of a disease [PP2]. Based on the clinical correlation and available evidence, and in absence of parental segregation, this variant is classified as "Likely Pathogenic" -

Jul 17, 2023

Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The variant is absent from gnomAD population databases and is located in a mutational hotspot. Alternative variants affecting the same amino at the specific position have previously been determined to be pathogenic while the prevalence of the variant in affected individuals is increased compared with the prevalence in controls. Computational tools also classify this change as moderate pathogenic. -

Apr 09, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Epileptic encephalopathy Pathogenic:1

Nov 16, 2016

Neurogenetics Laboratory - MEYER, AOU Meyer

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D;.;T;.;D;D;.;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;D;.;.;.;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	.;M;M;.;M;M;M;M;.
PhyloP100		10
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.96	N;N;.;.;.;.;N;N;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;D;.
Sift4G	Uncertain	0.0020	D;D;.;.;D;.;D;D;D
Polyphen		1.0	.;D;D;.;D;D;D;D;.
Vest4		0.72, 0.75, 0.72, 0.72
MutPred		0.67		Gain of ubiquitination at K246 (P = 0.107);Gain of ubiquitination at K246 (P = 0.107);Gain of ubiquitination at K246 (P = 0.107);.;Gain of ubiquitination at K246 (P = 0.107);Gain of ubiquitination at K246 (P = 0.107);Gain of ubiquitination at K246 (P = 0.107);Gain of ubiquitination at K246 (P = 0.107);.;
MVP		0.97
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.72
gMVP		0.93
Mutation Taster		=0/100	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: rs1057519528; hg19: chr2-166166886; COSMIC: COSV106088359;