rs149987700

Variant names:

• chr2-165310577-G-A
• rs149987700
• NM_001040142.2:c.952G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-165310577-G-A
• chr2-165310577-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP2 BP4 BP6 BS1 BS2

The NM_001040142.2(SCN2A):​c.952G>A​(p.Glu318Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000178 in 1,611,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 4.93
• Publications: 5 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

Our verdict: Benign. The variant received -9 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30324847).
• BP6: Variant 2-165310577-G-A is Benign according to our data. Variant chr2-165310577-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207045.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000224 (34/152054) while in subpopulation NFE AF = 0.000456 (31/67998). AF 95% confidence interval is 0.00033. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 34 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.952G>A	p.Glu318Lys	missense	Exon 7 of 27	NP_001035232.1	Q99250-1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.952G>A	p.Glu318Lys	missense	Exon 7 of 27	NP_001358175.1	Q99250-2
	SCN2A	NM_001040143.2		c.952G>A	p.Glu318Lys	missense	Exon 8 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.952G>A	p.Glu318Lys	missense	Exon 7 of 27	ENSP00000364586.2	Q99250-1
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.952G>A	p.Glu318Lys	missense	Exon 7 of 27	ENSP00000486885.1	Q99250-2
	SCN2A	ENST00000283256.10	TSL:1	c.952G>A	p.Glu318Lys	missense	Exon 7 of 27	ENSP00000283256.6	Q99250-1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.000456

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 249716 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000173 AC: 253 AN: 1458984 Hom.: 0 Cov.: 30 AF XY: 0.000164 AC XY: 119 AN XY: 725926

African (AFR) AF: 0.0000300 AC: 1 AN: 33382

American (AMR) AF: 0.0000673 AC: 3 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000218 AC: 242 AN: 1109902

Other (OTH) AF: 0.0000996 AC: 6 AN: 60266

GnomAD4 genome AF: 0.000224 AC: 34 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74274

African (AFR) AF: 0.0000483 AC: 2 AN: 41420

American (AMR) AF: 0.0000656 AC: 1 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000273

EpiControl AF: 0.000534

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	SCN2A-related disorder (1)
-	-	1	Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	0.062
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.76	N
PhyloP100		4.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.55
Sift	Benign	0.066	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.28
MVP		0.68
ClinPred		0.078	T
GERP RS		5.3
Varity_R		0.32
gMVP		0.88
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs149987700; hg19: chr2-166167087;