chr2-165388720-T-A

Variant names:

• chr2-165388720-T-A
• rs2060198
• NM_001040142.2:c.4914T>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001040142.2(SCN2A):​c.4914T>A​(p.Arg1638Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,746 control chromosomes in the GnomAD database, including 66,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5375 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61498 hom.)
• Consequence: SCN2A NM_001040142.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.217
• 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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-165388720-T-A is Benign according to our data. Variant chr2-165388720-T-A is described in ClinVar as Benign. ClinVar VariationId is 130223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.217 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

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.4914T>A	p.Arg1638Arg	synonymous	Exon 27 of 27	NP_001035232.1	Q99250-1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.4914T>A	p.Arg1638Arg	synonymous	Exon 27 of 27	NP_001358175.1	Q99250-2
	SCN2A	NM_001040143.2		c.4914T>A	p.Arg1638Arg	synonymous	Exon 28 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.4914T>A	p.Arg1638Arg	synonymous	Exon 27 of 27	ENSP00000364586.2	Q99250-1
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.4914T>A	p.Arg1638Arg	synonymous	Exon 27 of 27	ENSP00000486885.1	Q99250-2
	SCN2A	ENST00000283256.10	TSL:1	c.4914T>A	p.Arg1638Arg	synonymous	Exon 27 of 27	ENSP00000283256.6	Q99250-1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38787 AN: 151906 Hom.: 5374 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.255

GnomAD2 exomes AF: 0.283 AC: 71245 AN: 251338 AF XY: 0.291

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.308

Gnomad EAS exome AF: 0.215

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.287 AC: 418992 AN: 1461722 Hom.: 61498 Cov.: 38 AF XY: 0.289 AC XY: 210420 AN XY: 727160

African (AFR) AF: 0.168 AC: 5622 AN: 33474

American (AMR) AF: 0.228 AC: 10173 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 7974 AN: 26128

East Asian (EAS) AF: 0.313 AC: 12429 AN: 39688

South Asian (SAS) AF: 0.334 AC: 28846 AN: 86252

European-Finnish (FIN) AF: 0.408 AC: 21791 AN: 53418

Middle Eastern (MID) AF: 0.339 AC: 1952 AN: 5766

European-Non Finnish (NFE) AF: 0.282 AC: 313060 AN: 1111914

Other (OTH) AF: 0.284 AC: 17145 AN: 60378

GnomAD4 genome AF: 0.255 AC: 38791 AN: 152024 Hom.: 5375 Cov.: 32 AF XY: 0.261 AC XY: 19379 AN XY: 74300

African (AFR) AF: 0.168 AC: 6988 AN: 41486

American (AMR) AF: 0.225 AC: 3440 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1090 AN: 3468

East Asian (EAS) AF: 0.247 AC: 1272 AN: 5146

South Asian (SAS) AF: 0.318 AC: 1528 AN: 4812

European-Finnish (FIN) AF: 0.409 AC: 4327 AN: 10574

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19214 AN: 67970

Other (OTH) AF: 0.253 AC: 532 AN: 2106

Alfa AF: 0.282 Hom.: 2034

Bravo AF: 0.236

Asia WGS AF: 0.270 AC: 939 AN: 3478

EpiCase AF: 0.283

EpiControl AF: 0.278

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Seizures, benign familial infantile, 3 (2)
-	-	1	Developmental and epileptic encephalopathy, 11 (1)
-	-	1	Episodic ataxia, type 9 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (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
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.0
DANN	Benign	0.65
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs2060198; hg19: chr2-166245230; COSMIC: COSV51843027;