chr2-165344715-A-G

Variant names:

• chr2-165344715-A-G
• rs2228980
• NM_001040142.2:c.2723A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The c.2723A>G variant in SCN2A is a missense variant predicted to cause substitution of lysine by arginine at amino acid 908 (p.Lys908Arg). This variant is present in gnomAD v2.1 at an allele frequency of 0.4% (1190/282874 alleles), with the highest sub-population minor allele frequency of 0.6% in the European (non-Finnish) population, which exceeds the ClinGen Epilepsy Sodium Channel threshold (0.01%) for BA1. Additionally, gnomAD v2.1.1 reports 7 individuals with this variant in a homozygous state (BS1). In summary, this variant meets the criteria to be classified as Benign for AUTOSOMAL DOMINANT COMPLEX NEURODEVELOPMENTAL DISORDER based on the ACMG/AMP criteria applied, as specified by the ClinGen Epilepsy Sodium Channel VCEP: BA1, BS1 (VCEP specifications version 1.0; 6/13/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA155058/MONDO:0100038/068

• Frequency:
  • Genomes: 𝑓 0.0037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (37 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: 4.07
• Publications: 13 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 Submitted by: ClinGen, Illumina
• developmental and epileptic encephalopathy, 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -12 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.2723A>G	p.Lys908Arg	missense	Exon 16 of 27	NP_001035232.1
	SCN2A	NM_001371246.1	MANE Plus Clinical	c.2723A>G	p.Lys908Arg	missense	Exon 16 of 27	NP_001358175.1
	SCN2A	NM_001040143.2		c.2723A>G	p.Lys908Arg	missense	Exon 17 of 28	NP_001035233.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN2A	ENST00000375437.7	TSL:5 MANE Select	c.2723A>G	p.Lys908Arg	missense	Exon 16 of 27	ENSP00000364586.2
	SCN2A	ENST00000631182.3	TSL:5 MANE Plus Clinical	c.2723A>G	p.Lys908Arg	missense	Exon 16 of 27	ENSP00000486885.1
	SCN2A	ENST00000283256.10	TSL:1	c.2723A>G	p.Lys908Arg	missense	Exon 16 of 27	ENSP00000283256.6

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00578

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00437 AC: 1098 AN: 251494 AF XY: 0.00470

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00674

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00558 AC: 8155 AN: 1461888 Hom.: 37 Cov.: 31 AF XY: 0.00555 AC XY: 4039 AN XY: 727244

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.00326 AC: 146 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00472 AC: 407 AN: 86258

European-Finnish (FIN) AF: 0.00107 AC: 57 AN: 53420

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.00643 AC: 7147 AN: 1112008

Other (OTH) AF: 0.00510 AC: 308 AN: 60396

GnomAD4 genome AF: 0.00368 AC: 561 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.00334 AC XY: 249 AN XY: 74460

African (AFR) AF: 0.00130 AC: 54 AN: 41556

American (AMR) AF: 0.00432 AC: 66 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4820

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00578 AC: 393 AN: 68004

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00517 Hom.: 9

Bravo AF: 0.00432

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00491 AC: 596

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00523

EpiControl AF: 0.00634

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Seizures, benign familial infantile, 3 (2)
-	-	1	Complex neurodevelopmental disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 (1)
-	-	1	Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11;C5394520:Episodic ataxia, type 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.010	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.3	L
PhyloP100		4.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.015	D
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.24
MVP		0.97
ClinPred		0.024	T
GERP RS		5.7
Varity_R		0.63
gMVP		0.91
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2228980; hg19: chr2-166201225;