rs75057869

Positions:

• chr2-165389716-G-A

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.5910G>A​(p.Thr1970=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,613,752 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (42 hom.)
• Consequence: SCN2A NM_001040142.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.567

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=-0.49).
• BP6: Variant 2-165389716-G-A is Benign according to our data. Variant chr2-165389716-G-A is described in ClinVar as [Benign]. Clinvar id is 130225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165389716-G-A is described in Lovd as [Benign]. Variant chr2-165389716-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.567 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00229 (348/152060) while in subpopulation EAS AF= 0.0372 (192/5162). AF 95% confidence interval is 0.0329. There are 4 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 348 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.5910G>A	p.Thr1970=	synonymous_variant	27/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.5910G>A	p.Thr1970=	synonymous_variant	27/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.5910G>A	p.Thr1970=	synonymous_variant	27/27	5	NM_001040142.2	ENSP00000364586	P1
SCN2A	ENST00000631182.3	c.5910G>A	p.Thr1970=	synonymous_variant	27/27	5	NM_001371246.1	ENSP00000486885

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 347 AN: 151942 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0371

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00431 AC: 1082 AN: 250968 Hom.: 30 AF XY: 0.00409 AC XY: 555 AN XY: 135642

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0454

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000529

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00146 AC: 2132 AN: 1461692 Hom.: 42 Cov.: 32 AF XY: 0.00146 AC XY: 1060 AN XY: 727142

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.000828

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.0327

Gnomad4 SAS exome AF: 0.00368

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000171

Gnomad4 OTH exome AF: 0.00356

GnomAD4 genome AF: 0.00229 AC: 348 AN: 152060 Hom.: 4 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74346

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00197

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0372

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.000912 Hom.: 0

Bravo AF: 0.00253

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.000982

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 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

Feb 01, 2024

- -

Seizures, benign familial infantile, 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.49
CADD	Benign	0.52
DANN	Benign	0.74

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: rs75057869; hg19: chr2-166246226;