chr2-165331357-C-T

Variant names:

• chr2-165331357-C-T
• rs867268264
• NM_001040142.2:c.2177C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 5P and 8B. PM1 PP2 PP3_Moderate BS1 BS2

The NM_001040142.2(SCN2A):​c.2177C>T​(p.Pro726Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). The gene SCN2A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.91
• 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, 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001040142.2
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000958 (14/1461408) while in subpopulation MID AF = 0.00225 (13/5766). AF 95% confidence interval is 0.00133. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 14 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.2177C>T	p.Pro726Leu	missense	Exon 14 of 27	NP_001035232.1	Q99250-1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.2177C>T	p.Pro726Leu	missense	Exon 14 of 27	NP_001358175.1	Q99250-2
	SCN2A	NM_001040143.2		c.2177C>T	p.Pro726Leu	missense	Exon 15 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.2177C>T	p.Pro726Leu	missense	Exon 14 of 27	ENSP00000364586.2	Q99250-1
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.2177C>T	p.Pro726Leu	missense	Exon 14 of 27	ENSP00000486885.1	Q99250-2
	SCN2A	ENST00000283256.10	TSL:1	c.2177C>T	p.Pro726Leu	missense	Exon 14 of 27	ENSP00000283256.6	Q99250-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461408 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 726984

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111676

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	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	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.42	T
Polyphen		1.0	D
Vest4		0.62
MutPred		0.42		Loss of glycosylation at P726 (P = 0.0188)
MVP		0.92
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.96

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: rs867268264; hg19: chr2-166187867;