rs144814658

chr2-165295923-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_001040142.2(SCN2A):c.100G>A(p.Ala34Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00059 in 1,614,094 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A34V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 8.13

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 -10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_001040142.2
• PP2: Missense variant where missense usually causes diseases, SCN2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.033262193).
• BP6: Variant 2-165295923-G-A is Benign according to our data. Variant chr2-165295923-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207034.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=2, Likely_benign=3}. Variant chr2-165295923-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000598 (91/152258) while in subpopulation NFE AF= 0.000735 (50/68018). AF 95% confidence interval is 0.000573. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.100G>A	p.Ala34Thr	missense_variant	2/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.100G>A	p.Ala34Thr	missense_variant	2/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.100G>A	p.Ala34Thr	missense_variant	2/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.100G>A	p.Ala34Thr	missense_variant	2/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000689 AC: 173 AN: 251038 Hom.: 0 AF XY: 0.000627 AC XY: 85 AN XY: 135664

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.000599

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000590 AC: 862 AN: 1461836 Hom.: 1 Cov.: 31 AF XY: 0.000569 AC XY: 414 AN XY: 727216

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00440

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.000530

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74452

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000942 Hom.: 0

Bravo AF: 0.000631

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000733 AC: 89

EpiCase AF: 0.000981

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 28, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	SCN2A: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2019	This variant is associated with the following publications: (PMID: 22581653) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 29, 2015

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

SCN2A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Seizures, benign familial infantile, 3 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;.;.;.;.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.033	T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N;N;.;.;.;N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.056	T;T;.;.;.;T;T
Sift4G	Benign	0.14	T;T;.;T;.;T;T
Polyphen		1.0, 1.0	.;D;D;D;D;D;D
Vest4		0.36, 0.35, 0.36, 0.36
MVP		0.88
ClinPred		0.080	T
GERP RS		5.5
Varity_R		0.22
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs144814658; hg19: chr2-166152433;