rs374087499

Variant names:

• chr2-165996043-T-C
• rs374087499
• NM_001165963.4:c.4551A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001165963.4(SCN1A):​c.4551A>G​(p.Lys1517Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,609,700 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: SCN1A NM_001165963.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.608
• Publications: 0 publications found

Genes affected

SCN1A (HGNC:10585): (sodium voltage-gated channel alpha subunit 1) Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]

SCN1A-AS1 (HGNC:54069): (SCN1A and SCN9A antisense RNA 1)

LOC102724058 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-165996043-T-C is Benign according to our data. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-165996043-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 331883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.608 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000171 (26/151688) while in subpopulation SAS AF = 0.00538 (26/4832). AF 95% confidence interval is 0.00377. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 26 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN1A	NM_001165963.4	c.4551A>G	p.Lys1517Lys	synonymous_variant	Exon 27 of 29	ENST00000674923.1	NP_001159435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN1A	ENST00000674923.1	c.4551A>G	p.Lys1517Lys	synonymous_variant	Exon 27 of 29		NM_001165963.4	ENSP00000501589.1
SCN1A	ENST00000303395.9	c.4551A>G	p.Lys1517Lys	synonymous_variant	Exon 26 of 28	5		ENSP00000303540.4
SCN1A	ENST00000375405.7	c.4518A>G	p.Lys1506Lys	synonymous_variant	Exon 24 of 26	5		ENSP00000364554.3
SCN1A	ENST00000409050.2	c.4467A>G	p.Lys1489Lys	synonymous_variant	Exon 26 of 28	5		ENSP00000386312.1

Frequencies

GnomAD3 genomes AF: 0.000172 AC: 26 AN: 151570 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000439 AC: 110 AN: 250770 AF XY: 0.000598

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000234 AC: 341 AN: 1458012 Hom.: 2 Cov.: 29 AF XY: 0.000352 AC XY: 255 AN XY: 725368

African (AFR) AF: 0.00 AC: 0 AN: 33312

American (AMR) AF: 0.00 AC: 0 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.00373 AC: 321 AN: 86052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5738

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109260

Other (OTH) AF: 0.000266 AC: 16 AN: 60156

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151688 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74158

African (AFR) AF: 0.00 AC: 0 AN: 41488

American (AMR) AF: 0.00 AC: 0 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67696

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.00116 AC: 4 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Migraine, familial hemiplegic, 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 15, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Developmental and epileptic encephalopathy Benign:1

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Generalized epilepsy with febrile seizures plus, type 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Epilepsy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.65
PhyloP100		0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs374087499; hg19: chr2-166852553;