rs200138205

Variant names:

• chr2-165365200-G-A
• rs200138205
• NM_001040142.2:c.3457G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-165365200-G-A
• chr2-165365200-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP6 BS1 BS2

The NM_001040142.2(SCN2A):​c.3457G>A​(p.Glu1153Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,613,778 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1153V) has been classified as Uncertain significance. The gene SCN2A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:5
• Conservation: PhyloP100: 8.02
• Publications: 12 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, STRONG Submitted by: Illumina, ClinGen, PanelApp Australia
• developmental and epileptic encephalopathy, 11

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

Specifications for SCN2A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• 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 complex neurodevelopmental disorder, seizures, benign familial infantile, 3, episodic ataxia, type 9, developmental and epileptic encephalopathy, 11, malignant migrating partial seizures of infancy, intellectual disability, Dravet syndrome, infantile spasms, benign familial infantile epilepsy, benign familial neonatal-infantile seizures, genetic developmental and epileptic encephalopathy.
• BP6: Variant 2-165365200-G-A is Benign according to our data. Variant chr2-165365200-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206987.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000184 (28/152102) while in subpopulation NFE AF = 0.000368 (25/68016). AF 95% confidence interval is 0.000255. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 28 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040142.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN2A	NM_001040142.2	MANE Select	c.3457G>A	p.Glu1153Lys	missense	Exon 18 of 27	NP_001035232.1	Q99250-1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.3457G>A	p.Glu1153Lys	missense	Exon 18 of 27	NP_001358175.1	Q99250-2
	SCN2A	NM_001040143.2		c.3457G>A	p.Glu1153Lys	missense	Exon 19 of 28	NP_001035233.1	Q99250-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN2A	ENST00000375437.7	TSL:5 MANE Select	c.3457G>A	p.Glu1153Lys	missense	Exon 18 of 27	ENSP00000364586.2	Q99250-1
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.3457G>A	p.Glu1153Lys	missense	Exon 18 of 27	ENSP00000486885.1	Q99250-2
	SCN2A	ENST00000283256.10	TSL:1	c.3457G>A	p.Glu1153Lys	missense	Exon 18 of 27	ENSP00000283256.6	Q99250-1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000171 AC: 43 AN: 251444 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000387 AC: 566 AN: 1461676 Hom.: 1 Cov.: 32 AF XY: 0.000371 AC XY: 270 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53394

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000472 AC: 525 AN: 1111878

Other (OTH) AF: 0.000563 AC: 34 AN: 60380

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74314

African (AFR) AF: 0.0000483 AC: 2 AN: 41426

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000600

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	2	-	Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 (2)
-	1	-	Developmental and epileptic encephalopathy, 11 (1)
-	-	1	not specified (1)
-	-	1	SCN2A-related disorder (1)
-	-	1	Seizures, benign familial infantile, 3 (1)
-	1	-	Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11;C5394520:Episodic ataxia, type 9 (1)
1	-	-	Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.034	D
Polyphen		0.94	P
Vest4		0.31
MVP		0.85
ClinPred		0.31	T
GERP RS		5.8
Varity_R		0.48
gMVP		0.65
Mutation Taster		=42/58	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: rs200138205; hg19: chr2-166221710; COSMIC: COSV51838476;