rs2228980

chr2-165344715-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 5P and 20B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001040142.2(SCN2A):c.2723A>G(p.Lys908Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0054 in 1,614,136 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K908E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (37 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.07

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 Benign. Variant got -15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001040142.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-165344714-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 206976.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, SCN2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.01035431).
• BP6: Variant 2-165344715-A-G is Benign according to our data. Variant chr2-165344715-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 130219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165344715-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00368 (561/152248) while in subpopulation NFE AF= 0.00578 (393/68004). AF 95% confidence interval is 0.00531. There are 0 homozygotes in gnomad4. There are 249 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 560 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.2723A>G	p.Lys908Arg	missense_variant	16/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.2723A>G	p.Lys908Arg	missense_variant	16/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.2723A>G	p.Lys908Arg	missense_variant	16/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.2723A>G	p.Lys908Arg	missense_variant	16/27	5	NM_001371246.1

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

GnomAD3 exomes AF: 0.00437 AC: 1098 AN: 251494 Hom.: 7 AF XY: 0.00470 AC XY: 639 AN XY: 135920

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 SAS exome AF: 0.00447

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

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00472

Gnomad4 FIN exome AF: 0.00107

Gnomad4 NFE exome AF: 0.00643

Gnomad4 OTH exome AF: 0.00510

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

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00578

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00525 Hom.: 6

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

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SCN2A: PM5, PP2, BS1, BS2 -

Seizures, benign familial infantile, 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11;C5394520:Episodic ataxia, type 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 02, 2021

- -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;D;D;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T;.;T;.;.;.;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.3	L;L;.;L;L;L;L
MutationTaster	Benign	0.68	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.2	N;.;.;.;.;N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.015	D;.;.;.;.;D;D
Sift4G	Benign	0.24	T;.;.;T;.;T;T
Polyphen		1.0	D;B;.;B;D;D;B
Vest4		0.24
MVP		0.97
ClinPred		0.024	T
GERP RS		5.7
Varity_R		0.63
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228980; hg19: chr2-166201225;