rs199698414

Variant names:

• chr2-165388961-T-A
• NM_001040142.2:c.5155T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-165388961-T-A
• chr2-165388961-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001040142.2(SCN2A):​c.5155T>A​(p.Leu1719Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L1719L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.511

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.5155T>A	p.Leu1719Met	missense_variant	Exon 27 of 27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.5155T>A	p.Leu1719Met	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.5155T>A	p.Leu1719Met	missense_variant	Exon 27 of 27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.5155T>A	p.Leu1719Met	missense_variant	Exon 27 of 27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.5155T>A	p.Leu1719Met	missense_variant	Exon 27 of 27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;.;T;.;D;D;.
Eigen	Benign	0.070
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.76	T;.;T;.;.;.;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.4	M;M;.;M;M;M;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.8	N;.;.;.;.;N;N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Benign	0.14	T;.;.;T;.;T;T
Polyphen		1.0	D;D;.;D;D;D;D
Vest4		0.55
MutPred		0.52		Gain of disorder (P = 0.1255);Gain of disorder (P = 0.1255);.;Gain of disorder (P = 0.1255);Gain of disorder (P = 0.1255);Gain of disorder (P = 0.1255);Gain of disorder (P = 0.1255);
MVP		0.96
ClinPred		0.96	D
GERP RS		0.47
Varity_R		0.64
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-166245471;