rs147891446

Positions:

• chr2-165326869-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001040142.2(SCN2A):​c.2034A>G​(p.Thr678Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00746 in 1,613,978 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (80 hom.)
• Consequence: SCN2A NM_001040142.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0120

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-165326869-A-G is Benign according to our data. Variant chr2-165326869-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 139032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165326869-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.012 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00523 (796/152336) while in subpopulation SAS AF= 0.0166 (80/4830). AF 95% confidence interval is 0.0136. There are 4 homozygotes in gnomad4. There are 369 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 796 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.2034A>G	p.Thr678Thr	synonymous_variant	13/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.2034A>G	p.Thr678Thr	synonymous_variant	13/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.2034A>G	p.Thr678Thr	synonymous_variant	13/27	5	NM_001040142.2	ENSP00000364586.2
SCN2A	ENST00000631182.3	c.2034A>G	p.Thr678Thr	synonymous_variant	13/27	5	NM_001371246.1	ENSP00000486885.1
SCN2A	ENST00000283256.10	c.2034A>G	p.Thr678Thr	synonymous_variant	13/27	1		ENSP00000283256.6

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 796 AN: 152218 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00729

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00655 AC: 1647 AN: 251352 Hom.: 9 AF XY: 0.00735 AC XY: 998 AN XY: 135826

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0187

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00739

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00769 AC: 11237 AN: 1461642 Hom.: 80 Cov.: 32 AF XY: 0.00807 AC XY: 5865 AN XY: 727108

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0185

Gnomad4 FIN exome AF: 0.00367

Gnomad4 NFE exome AF: 0.00786

Gnomad4 OTH exome AF: 0.00624

GnomAD4 genome AF: 0.00523 AC: 796 AN: 152336 Hom.: 4 Cov.: 32 AF XY: 0.00495 AC XY: 369 AN XY: 74488

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00729

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00607 Hom.: 3

Bravo AF: 0.00484

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2012	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	Athena Diagnostics	Sep 17, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2015	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2016

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.8
DANN	Benign	0.81

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: rs147891446; hg19: chr2-166183379;